Asymmetric bifunctional silyl monomers and particles thereof as prodrugs and delivery vehicles for pharmaceutical, chemical and biological agents

ABSTRACT

Asymmetric bifunctional silyl (ABS) monomers comprising covalently linked pharmaceutical, chemical and biological agents are described. These agents can also be covalently bound via the silyl group to delivery vehicles for delivering the agents to desired targets or areas. Also described are delivery vehicles which contain ABS monomers comprising covalently linked agents and to vehicles that are covalently linked to the ABS monomers. The silyl modifications described herein can modify properties of the agents and vehicles, thereby providing desired solubility, stability, hydrophobicity and targeting.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/482,624, filed Sep. 10, 2014, which is a continuation of U.S.National Stage application Ser. No. 13/523,559, filed Apr. 29, 2013,which is based on International Patent Application No.PCT/US2011/051775, filed Sep. 15, 2011, which claims the benefit of U.S.Provisional Application No. 61/383,651, filed Sep. 16, 2010, all ofwhich are herein incorporated by reference in their entirety.

GOVERNMENT SUPPORT

This invention was made with government support under Grants1-DP1-OD006432-01, CA119343 and CA151652 awarded by the NationalInstitutes of Health. The government has certain rights in theinvention.

FIELD OF THE INVENTION

The subject matter herein is directed to asymmetric bifunctional silyl(ABS) monomers, such as silyl ether containing pharmaceutical, chemicaland biological agents and delivery vehicles for these agents as well asABS modified delivery vehicles themselves, such as liposomes andnanoparticles.

BACKGROUND

Drug delivery technology has been exploited extensively for the purposeof delivering agents to desired targets for many years. Drug deliverytechnologies involve liposomes and nano or microparticles. Hydrophobicor hydrophilic compounds can be entrapped in the hydrophobic domain orencapsulated in the aqueous compartment, respectively. Liposomes can beconstructed of natural constituents so that the liposome membrane is inprincipal identical to the lipid portion of natural cell membranes. Itis considered that liposomes are quite compatible with the human bodywhen used as drug delivery systems.

The cellular delivery of various therapeutic compounds, such aschemotherapeutic agents, is usually compromised by two limitations.First, the selectivity of a number of therapeutic agents is often low,resulting in high toxicity to normal tissues. Secondly, the traffickingof many compounds into living cells is highly restricted by the complexmembrane systems of the cell. Specific transporters allow the selectiveentry of nutrients or regulatory molecules, while excluding mostexogenous molecules such as nucleic acids and proteins.

The problems mentioned above are not adequately addressed by existingdelivery vehicles or compositions. The presently disclosed subjectmatter addresses, in whole or in part, these and other needs in the art.

SUMMARY OF THE INVENTION

Asymmetric bifunctional silyl (ABS) monomers containing pharmaceutical,chemical and biological agents are described. These agents can becovalently bound via the Si atom, for example with a silyl etherlinkage. The monomers themselves can be covalently bound via the Si atomto delivery vehicles, such as particles, for delivering the agents todesired targets or areas. Also described are delivery vehicles whichcontain an agent having a silyl ether linkage and to vehicles that arecovalently linked to the silyl ether agent. The (ABS) modified agentsdescribed herein provide modified properties of the agents and vehicles,thereby providing desired solubility, stability, hydrophobicity andtargeting.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a representative group of amino acids that provide sitesfor silyl attachment.

FIG. 2 depicts the preparation of asymmetric bifunctional silyl (ABS)monomers and their incorporation into a polymer particle. In eachinstance, the monomer residue and the drug residue may be the same ordifferent from other ABS monomers within the polymer particle.

FIGS. 3A-D depict high performance liquid chromatograms of HEA,camptothecin, Et-CPT ABS prodrug, and the pro-drug after exposure toacid.

FIG. 4 depicts a percent release of gemcitabine vs time for 200 nm×200nm PRINT particles fabricated from Et-GEM (circle), iPr-GEM (triangle),and tBu-GEM (diamond) ABS pro-drugs. Closed symbols represent particlesdegraded at pH 5.0 and open symbols represent particles degraded at pH7.4.

FIG. 5 depicts a percent viability of H460 cells against PRINT particlescontaining 2 wt % and 20 wt % ABS pro-drug. The particles were comparedagainst free camptothecin and free CPT-ABS pro-drug.

FIG. 6 shows the data from a cell viability assay (CellTiter-Glo) of 200nm×200 nm PRINT particles fabricated from Et-GEM (Diamond), iPr-GEM(square), and tBu-GEM (triangle) ABS pro-drugs versus blank particles(X) and free gemcitabine (*). The assay was performed using LnCAP cells.

FIGS. 7A-B depict % cell viability versus particle concentration (μg/mL)containing ABS (diethyl) CPT (camptothecin) or ABS (di-iPr) CPT.

FIGS. 8-11 depict drugs and compounds that, in some embodiments, can becovalently bound to form ABS monomers and particle thereof.

FIG. 12 depicts in vitro selective targeting of OKT9-targeted particlesin H460 cells that can be inhibited by competitive binding from freeligand.

FIG. 13 depicts the selective targeting of OKT9-targeted particlesobserved by confocal microscopy. At 4 h, binding and someinternalization of OKT9-targeted particles is observed, while increasedinternalization and colocalization is seen at 24 h. IgG-targetedparticles do not bind and internalize into the cells.

FIG. 14 depicts the cytotoxicity profiles of H460 cells treated withtargeted particles containing prodrug. OKT9-targeted particles exhibitenhanced and selective cytotoxicity over free gemcitabine andIgG-targeted particles because of its specific targeting ligands andincorporation of an ABS prodrug.

DETAILED DESCRIPTION

The presently disclosed subject matter will now be described more fullyhereinafter. However, many modifications and other embodiments of thepresently disclosed subject matter set forth herein will come to mind toone skilled in the art to which the presently disclosed subject matterpertains having the benefit of the teachings presented in the foregoingdescriptions. Therefore, it is to be understood that the presentlydisclosed subject matter is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.

The tailorable ABS pro-drugs, monomers and particles described hereinprovide effective modifications of a parent drug, particle, such asmolded particles to prepare compositons for targeted delivery of a drugor cargo. Advantages of the presently disclosed ABS compositionsinclude: one-pot synthesis of ABS pro-drugs, monomers and particles;tunable release kinetics; wide ranges of biocompatibility; release ofparent drug; stability under physiological conditions up to the desiredtarget; higher drug loading over conventional silyl linked drugs; andtargeted degradation under certain acidic conditions.

Disclosed herein are agents and delivery vehicles that have desirableproperties. These properties are provided by covalently linking a silylmoiety to the agent or vehicle or both via covalent bond(s).

In embodiments, the present subject matter is directed to afunctionalized drug delivery monomer comprising an asymmetricbifunctional silyl (ABS) prodrug having a formula.

wherein R^(1′) and R^(2′) are independently selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl,alkaryl, and a hydrophobic group, preferably R^(1′) and R^(2′) areindependently selected from a C₁₋₄ alkyl;

wherein M is a residue of one of the following selected from the groupconsisting of a hydrogel, 2-Hydroxyethyl acrylate, 2-Hydroxyethylmethacrylate, vinyl pyrrolidone, acrylic acid, ethylene oxide orPoly(ethylene oxide) monomers, vinyl alcohol, a protein, an amino acid,and a polysaccharide;

wherein X_(a) and X_(b) are each independently selected from the groupconsisting of O, NH, S, and a carboxyl (COO); and

wherein R^(3′) is selected from the group consisting of a drug, abiologic, or fragments thereof.

In preferred monomers, at least one of X_(a) and X_(b) is O. Morepreferably, X_(a) and X_(b) are each O.

The ABS monomers described herein can advantageously be employed toprepare polymers containing any number of different ABS monomer units,wherein each monomer's components, i.e., specific values for the M, Xand R′ variables, can be independently selected from any other monomer'scomponents. For example, an ABS monomer's component M can be selectedfrom M₁, M₁, M₃, M₄ and so on. A second ABS monomer's component M can bethe same or different from the first monomer's M component. Likewise, Xand R′ variables can be independently selected for each monomer. Theadvantageous result is highly tunable monomer units. These units, inturn, can be used to prepare uniquely tunable polymers by selecting thedesired monomers to form the polymer. This is a superior method ofpreparing polymers because it yields a polymer containing not onlydifferent cargos, e.g. drugs, but the polymer can also exhibit differentrelease rates for each cargo. Moreover, the amounts of cargo that can beincorporated into the polymer are substantially higher using the presentmethod up to about 50 wt. %.

In embodiments, the present subject matter is directed to one or moremolded polymer particles comprising ABS pro-drugs and/or ABS-monomers.Advantageously, the particles can comprise different ABS monomers andthe corresponding covalently attached drug/cargo. As described herein,the monomers are tunable. In turn, preparing the present particles fromthe ABS monomers provides methods for incorporating many types ofmonomers and cargos in a single particle. Consequently, the particlesthemselves are highly tunable and novel. Indeed, the load of cargomeasured by a ratio or wt. % of the present particles is superior. Thepresent particles comprise a crosslinked network of the ABS monomers.Methods of preparing particles are described in US 2009/0028910; US2009/0061152; WO 2007/024323; US 2009/0220789; US 2007/0264481; US2010/0028994; US 2010/0196277; WO 2008/106503; US 2010/0151031; WO2008/100304; WO 2009/041652; PCT/US2010/041797; US 2008/0181958; WO2009/111588; and WO 2009/132206, each of which is hereby incorporated byreference in their entirety.

Preferably, the particles contain a cargo, such as an ABS pro-drug,which comprises a ratio of about 0.1 mg of drug to about 1 mg ofparticle. Also preferred are particles wherein the cargo, such as an ABSpro-drug, comprises from about 1 wt. % to about 50 wt. % of theparticle; from about 1 wt. % to about 40 wt. % of the particle; fromabout 2 wt. % to about 20 wt. % of the particle; from about 3 wt. % toabout 50 wt. %; from about 4 wt. % to about 50 wt. % of the particle;from about 5 wt. % to about 50 wt. % of the particle; from about 5 wt. %to about 25 wt. % of the particle; from about 5 wt. % to about 20 wt. %;and from about 5 wt. % to about 15 wt. % of the particle.

The particles are preferably molded wherein the molded particle furthercomprises a three-dimensional shape substantially mimicking the moldshape and a size less than about 50 micrometers in a broadest dimension.In further embodiments, the particles are preferably molded to have athree-dimensional shape substantially mimicking the mold shape and asize less than about 5 micrometers in a broadest dimension. Preferably,the molded particles have a first dimension of less than about 200nanometers and a second dimension greater than about 200 nanometers.

In an embodiment, a molded particle comprises, two or more asymmetricbifunctional silyl pro-drug monomers having a formula

wherein, in each monomer, R^(1′) and R^(2′), in each instance, areindependently selected from the group consisting of alkyl, cycloalkyl,alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group,preferably both R^(1′) and R^(2′) are independently selected from a C₁₋₄alkyl,

wherein, in each monomer, M is a residue of one of the followingselected from the group consisting of a hydrogel, 2-Hydroxyethylacrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid,ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, aprotein, an amino acid, and a polysaccharide;

wherein, in each monomer, X_(a) and X_(b), in each instance, are eachindependently selected from the group consisting of O, NH, S, and acarboxyl; and

wherein, in each monomer, R^(3′) in each instance, is selected from thegroup consisting of a drug, a biologic, or fragments thereof,

wherein in each monomer, the variables M and drug can be independentlyselected from each other monomer.

In another embodiment, the present subject matter is directed to amolded particle comprising,

a first asymmetric bifunctional silyl pro-drug monomer having thestructure

and

a second asymmetric bifunctional silyl pro-drug monomer having thestructure

wherein, in each monomer, R^(1′) and R^(2′), in each instance, areindependently selected from the group consisting of alkyl, cycloalkyl,alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group,preferably both R^(1′) and R^(2′) are independently selected from a C₁₋₄alkyl;

wherein, in each monomer, M₁ or M₂ is a residue of one of the followingselected from the group consisting of a hydrogel, 2-Hydroxyethylacrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid,ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, aprotein, an amino acid, and a polysaccharide;

wherein, in each monomer, X_(a) and X_(b), in each instance, are eachindependently selected from the group consisting of O, NH, S, and acarboxyl; and

wherein, in each monomer, R^(3′A) or R^(3′B), in each instance, isselected from the group consisting of a drug, a biologic, or fragmentsthereof,

wherein,

-   -   i. M₁ and M₂ are different,    -   ii. R^(3′A) and R^(3′B) are different,    -   iii. M₁ and M2 are the same, and R^(3′A) and R^(3′B) are        different,

or

-   -   iv. M₁ and M2 are different, and R^(3′A) and R^(3′B) are the        same.

In another aspect of this embodiment, the molded particle can furthercomprise a third asymmetric bifunctional silyl pro-drug monomer havingthe structure

wherein, in each monomer, R^(1′) and R^(2′), in each instance, areindependently selected from the group consisting of alkyl, cycloalkyl,alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group,preferably both R^(1′) and R^(2′) are independently selected from a C₁₋₄alkyl;

wherein, in each monomer, M3 is a residue of one of the followingselected from the group consisting of a hydrogel, 2-Hydroxyethylacrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid,ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, aprotein, an amino acid, and a polysaccharide;

wherein, in each monomer, X_(a) and X_(b), in each instance, are eachindependently selected from the group consisting of O, NH, S, and acarboxyl; and

wherein, in each monomer, R^(3′C), in each instance, is selected fromthe group consisting of a drug, a biologic, or fragments thereof,

wherein,

-   -   i. M₁ and M2 are different than M3,

or

-   -   ii. R^(3′A) and R^(3′B) are different than R^(3′C).

The present particle can contain a fourth, fifth, sixth and so onasymmetric bifunctional silyl pro-drug monomer. Each monomer can beindividualized by selecting desried values for each variable M, X andR′. Accordingly, the polymers/particles prepared from these monomers caninclude any number of cargos/drugs and, of course, are tunablethemselves given the tenability of the monomers components.

A feature of the present particles is their release rates. In apreferred embodiment, R^(1′) and R^(2′) of the ABS monomer are eachethyl and the polymer particle formed therefrom has a release rate of2.87 at pH 7.4 relative to a release rate at pH 5.0 of a particle havingR^(1′) and R^(2′) of ethyl. In another preferred embodiment, wherein R¹and R² are isopropyl, the particle has a release rate of 50.4 at pH 5.0and 201 at pH 7.4 relative to a release rate at pH 5.0 of a particlehaving R^(1′) and R^(2′) of ethyl. In another preferred embodimentwherein R^(1′) and R^(2′) are t-butyl, the particle has a release rateof 4968 at pH 5.0 and 9675 at pH 7.4 relative to a release rate at pH5.0 of a particle having R^(1′) and R^(2′) of ethyl.

In an embodiment, the present subject matter is directed to acomposition comprising a plurality of substantially identically sizedand shaped molded particles as described herein.

In embodiments, the present subject matter is directed to methods ofpreparing an ABS pro-drug or ABS monomer, the methods comprising,

covalently linking a monomer and a silyl via an O, N, S or carboxyl ofsaid monomer to prepare a silyl monomer;

covalently linking a drug to said silyl monomer to prepare a drug-silylmonomer;

cross-linking at least one of said drug-silyl monomers to another saiddrug-silyl monomer, to form a polymer wherein the monomer and/or thedrug can be different in each drug-silyl monomer, wherein each of saidcovalent linkages is reversible. Preferably, the monomer is degradable.

Preferably, the covalent linking of the monomer with the silyl is via acarbon-oxygen bond.

In another embodiment, the present subject matter is directed to amethod for reversibly modifying a characteristic of a particlecomprising,

-   -   i. reversibly bonding a silyl group with a particle through a        covalent bond, wherein said particle comprises a drug; and    -   ii. reversibly bonding to said silyl group a lipid or polymer        through a covalent bond;        wherein the lipid or polymer modifies a characteristic of said        particle, wherein i. and ii. can be performed in any order. The        method can further comprise reversing the covalent bonds in any        manner thereby releasing the parent cargo/drug or lipid or        polymer. The covalent bonds are selected from Si—O; Si—N; Si—S        or Si—COO.

Useful chracteristics of a particle that can be modified include thehydrophobic or hydrophilic characteristic of the particle. Known lipidsand polymers in the art can be used via the chemical handles on theparticles and the lipid or polymer itself by the methods describedherein as well as the information incorporated by reference.

In some embodiments of the present invention, reversible silyl ether,silyl ester, silyl amine or silyl thio ether moieties are attached tothe surface of a particle to attach i) lipids, ii) water solublepolymers (e.g. poly(ethylene glycol)), and iii) reversible silyl ether,ester, amine or thio ether pro-drugs with the particle and iv) targetingligands. Additionally, reversible silyl ether, ester, amine or thioether chemistry is used to iv) introduce silyl ether, ester, amine orthio ether pro-drugs to the interior of a nanoparticle. According tosuch embodiments, the particle can facilitate delivery of a cargo, suchas a drug for example, in vivo safely and securely until a give abiological or chemical condition is reached which triggers reversing ofthe link chemistry and therefore release of the cargo.

In embodiments, the present subject matter is directed to methods ofreversibly modifying a characteristic of an agent comprising,

-   -   i. reversibly bonding a silyl group with an agent through a        covalent bond; and    -   ii. reversibly bonding to the silyl group a lipid or polymer        through a covalent bond;        wherein the lipid or polymer modifies a characteristic of said        particle, wherein i. and ii. can be performed in any order. The        method can further comprise reversing the covalent bonds in any        manner thereby releasing the parent agent or lipid or polymer.        The covalent bonds are selected from Si—O; Si—N; Si—S or Si—COO.

Useful chracteristics of an agent that can be modified include thehydrophobic or hydrophilic characteristic of the agent. Known lipids andpolymers in the art can be used via the chemical handles on the agentand the lipid or polymer itself by the methods described herein as wellas the information incorporated by reference. The term “active”, “activeagent”, “active pharmaceutical agent”, “active drug” or “drug” as usedherein means any active pharmaceutical ingredient (“API”), including itspharmaceutically acceptable salts (e.g. the hydrochloride salts, thehydrobromide salts, the hydroiodide salts, and the saccharinate salts),as well as in the anhydrous, hydrated, and solvated forms, in the formof prodrugs, and in the individually optically active enantiomers of theAPI as well as polymorphs of the API.

As used herein the term “mammal” refers to humans as well as all othermammalian animals. As used herein, the term “mammal” includes a“subject” or “patient” and refers to a warm blooded animal.

As used herein, the terms “cancer” and “cancerous” refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include, but are notlimited to, melanoma, carcinoma, lymphoma, blastoma, sarcoma, andleukemia or lymphoid malignancies. More particular examples of cancersinclude squamous cell cancer (e.g., epithelial squamous cell cancer),lung cancer including small-cell lung cancer, non-small cell lungcancer, adenocarcinoma of the lung and squamous carcinoma of the lung,cancer of the peritoneum, hepatocellular cancer, gastric or stomachcancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial cancer or uterine carcinoma, salivary glandcarcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, aswell as head and neck cancer.

As used herein, the term “therapeutically effective” and “effectiveamount,” is defined as the amount of the pharmaceutical composition thatproduces at least some effect in treating a disease or a condition. Forexample, in a combination according to the invention, an effectiveamount is the amount required to inhibit the growth of cells of aneoplasm in vivo. The effective amount of active compound(s) used topractice the present invention for therapeutic treatment of neoplasms(e.g., cancer) varies depending upon the manner of administration, theage, body weight, and general health of the subject. It is within theskill in the art for an attending physician or veterinarian to determinethe appropriate amount and dosage regimen. Such amounts may be referredto as “effective” amounts.

An “active agent moiety” in reference to a prodrug conjugate of theinvention, refers to the portion or residue of the umodified parentactive agent up to the covalent linkage resulting from covalentattachment of the drug (or an activated or chemically modified formthereof) to a polymer of the invention. Upon hydrolysis of the linkagebetween the active agent moiety and the multi-armed polymer, the activeagent per se is released.

As used herein, the term “ligand” refers to a molecule that can be usedto target a desired area or tissue. The ligand will have an affinity forthe desired tissue based on intrinsic properties of the ligand and thetarget.

As used herein, “wt. %” can be determined by the weight of the silylpro-drug moeity covalently bound to the particle relative to the weightof the particle or the weight of particular ABS monomers incorporatedinto the polymer relative to the weight of the polymer particle.

As used herein, the term “substantially mimicking” means a moldedparticle that has a shape that is predetermined from the mold used toprepare the particle. This term includes variance in the shape, size,volume, etc. of the particle from the mold itself. However, theparticles shape, size, volume etc. cannot be random since they areprepared from molds and substantially mimic the mold's shape, size,volume, etc.

As used herein, the term “residue” refers to the parent drug, monomer orparticle wherein an O, N, S or carboxyl moiety on the parent iscovalently bound to a Si atom in the ABS molecule. Upon cleavage of thereversible Si bond and the residue, the parent drug, monomer or particleis released.

As used herein, the term “alkyl” refers to both straight, branchedcarbon chains and cyclic hydrocarbon groups; references to individualalkyl groups are specific for the straight chain (e.g. butyl=n-butyl).In one embodiment of alkyl, the number of carbons atoms is 1-20, inother embodiments of alkyl, the number of carbon atoms is 1-12, 1-10 or1-8 carbon atoms. In yet another embodiment of alkyl, the number ofcarbon atoms is 1-4 carbon atoms. Examples of C₁-C₁₀ alkyl include, butare not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups, which are encompassed by alkyls, are referred to as“cycloalkyl” and include those with 3 to 10 carbon atoms having singleor multiple fused rings. Non-limiting examples of cycloalkyl groupsinclude adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. In one embodiment ofalkenyl, the number of double bonds is 1-3, in another embodiment ofalkenyl, the number of double bonds is one. In one embodiment ofalkenyl, the number of carbons atoms is 2-20, in other embodiments ofalkenyl, the number of carbon atoms is 2-12, 2-10 or 2-8. In yet anotherembodiment of alkenyl, the number of carbon atoms is 2-4.“C₂-C₁₀-alkenyl” groups may include more than one double bond in thechain. Examples include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

The term “alkynyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon triple bond. In one embodiment ofalkynyl, the number of triple bonds is 1-3; in another embodiment ofalkynyl, the number of triple bonds is one. In one embodiment ofalkynyl, the number of carbons atoms is 2-20, in other embodiments ofalkynyl, the number of carbon atoms is 2-12, 2-10 or 2-8. In yet anotherembodiment of alkynyl, the number of carbon atoms is 2-4. The term“C₂-C₁₀-alkynyl” as used herein refers to a straight-chain or branchedunsaturated hydrocarbon group having 2 to 10 carbon atoms and containingat least one triple bond, such as ethynyl, prop-1-yn-1-yl,prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl,n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl,n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl,3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl,n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl,n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl,n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl,3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl,4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yland the like.

The term “aryl” refers to a C₆-C₁₄ aromatic carbocyclic ring structurehaving a single ring or multiple fused rings. Aryl groups include, butare not limited to, phenyl, biphenyl, and naphthyl. In some embodimentsaryl includes tetrahydronapthyl, phenylcyclopropyl and indanyl. Arylgroups may be unsubstituted or substituted by one or more moietiesselected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl,haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy,alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy,cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio,haloalkylthio, arylthio, cycloalkylthio, halocycloalkylthio,alkylsulfinyl, alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl,haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl, alkylcarbonyl,haloalkylcarbonyl, alkylamino, alkenylamino, alkynylamino,di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, or SF₅. In oneembodiment of aryl, the moiety is phenyl, naphthyl, tetrahydronapthyl,phenylcyclopropyl and indanyl; in another embodiment of aryl, the moietyis phenyl. The term “alkaryl” refers to an alkyl substituted aryl.

The term “aralkyl” refers to an alkyl where at least one hydrogen issubstituted with an aryl group. Examples include phenyl C₁₋₄ alkyl andbenzyl.

As used herein, a silyl ether, ester, amine or thio ether has thegeneral structure:

wherein R¹, R², R³ and R⁴ are independently hydrogen, alkyl or apharmaceutical, chemical or biological agent, wherein at least one ofR¹, R², R³ and R⁴ represents a pharmaceutical, chemical or biologicalagent and R⁴ represents a lipid, a tracer, a ligand, a particle asdescribed herein, a polymer, a monomer or a drug delivery vehicle. Inanother embodiment, when R⁴ represents a drug delivery vehicle, R¹ is apharmaceutical, chemical or biological agent, a lipid, a tracer or aligand and R¹ and R² are independently hydrogen or alkyl.

As used herein, a silyl ether, ester, amine or thio ether can also havethe general structure:

wherein M, X_(a), X_(b), R^(1′), R^(2′) and R^(3′) are as describedherein.

According to the present invention, generally any nucleophilic particlewill facilitate a silyl ether linkage. “Nucleophile” refers to an ion oratom or collection of atoms that may be ionic, having a nucleophiliccenter, i.e., a center that is seeking an electrophilic center, andcapable of reacting with an electrophile. “Electrophile” refers to anion, atom, or collection of atoms that may be ionic, having anelectrophilic center, i.e., a center that is electron seeking, capableof reacting with a nucleophile. Specifically, particles comprised ofpoly(alcohols), poly(amines), poly(carboxylates), and poly(thiols), andthe like will facilitate a silyl ether linkage. Compositions includingsugars (e.g. lactose, glucose,) polysaccharides (e.g. dextran,cyclodextran), glycerol, poly(ethylene glycol), poly(vinyl alcohol),poly(amino ethyl methacrylate), poly(aminopropyl methacrylate),poly(carboxyethyl acrylate) are ideal for this chemistry. In aparticular embodiment, a particle composition can include 40 wt % humanserum albumin, 40 wt % lactose and 20 wt % glycerol.

In one embodiment, a pharmaceutical, chemical or biological agent iscovalently linked to a silyl ether, ester, amine or thio ether moeity.In this embodiment, the resulting compound can act as a pro-drug of theagent. Thus, in structure I above, the residue of an agent can be R¹, R²or R³, wherein an atom on the agent is bound to the silicon atom. Theatom or moiety contained in the structure of the agent is generally anO, N, S or carboxyl, thereby forming a silyl ether, ester, amine or thioether bond. The remaining R groups can be unsubstituted or substitutedwith the variables described above. Methods of preparing such silylether, ester, amine or thio ether compounds, also referred to as ABSpro-drugs or ABS monomers, are described herein.

Additional specific embodiments of the present disclosure include: Adelivery vehicle for pharmaceutical, chemical or biological agents, saidvehicle comprising a silyl ether. Preferably in this delivery vehicle,the silyl ether is present on an exterior or interior surface of saidvehicle. Also preferred in this delivery vehicle, the silyl ether iscovalently linked to the exterior or interior surface. Preferably, thesilyl ether comprises a lipid, polymer, ligand, tracer, chemical agent,pharmaceutical agent or biological agent. Preferably, the polymer is awater soluble polymer. More preferably, the polymer is a PEG, PLGA,PMMA, or other biocompatible, biodegradable, or the like polymer. Usefuldelivery vehicles are selected from the group consisting of a liposome,particle, microparticle and nanoparticle. Most preferably, the vehicleis a molded micro- or nanoparticle.

Another embodiment is directed to a compound having a silyl ethercovalent linkage bound to a pharmaceutical, chemical or biologicalagent. In this embodiment, the silyl ether covalent linkage is bound toa pharmaceutical agent. Preferably, the pharmaceutical agent is selectedfrom the group consisting of analgesics, anti-cancer agents,anti-inflammatory agents, antihelminthics, anti-arrhythmic agents,anti-bacterial agents, anti-viral agents, anti-coagulants,anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents,anti-gout agents, anti-hypertensive agents, anti-malarials,anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents,erectile dysfunction improvement agents, immunosuppressants,anti-protozoal agents, anti-thyroid agents, anxiolytic agents,sedatives, hypnotics, neuroleptics, β-blockers, cardiac inotropicagents, corticosteroids, diuretics, anti-parkinsonian agents,gastro-intestinal agents, histamine receptor antagonists, keratolyptics,lipid regulating agents, anti-anginal agents, Cox-2 inhibitors,leukotriene inhibitors, macrolides, muscle relaxants, nutritionalagents, opioid analgesics, protease inhibitors, sex hormones,stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesityagents, cognition enhancers, anti-urinary incontinence agents,anti-benign prostate hypertrophy agents, essential fatty acids,non-essential fatty acids, and mixtures thereof. More preferably, thepharmaceutical agent is an anti-cancer agent. It is also preferred thatthe pharmaceutical or biological agent is selected from quinolinealkaloids, taxanes, anthracyclines, nucleosides, kinase inhibitors,tyrosine kinase inhibitors, antifolates, proteins and nucleic acids.More preferably, the pharmaceutical or biological agent is selected fromthe group consisting of Camptothecin, Topotecan, Irinotecan, SN-38,Paclitaxel, Docetaxel, Daunorubicin, Doxorubicin, Epirubicin, IdarubicinGemcitabine, Cytarabine, Brefeldin-A Imatinib, Gefitinib, Lapatinib,Sunitinib, Methotrexate, Folinic Acid, Efflux Inhibitors, ATP-BindingInhibitors, Cytochrome-C, Ovalbumin, siRNA Anti-Luciferase, siRNAAndrogen Receptor and RNA Replicon. Also preferred are compounds wherethe silyl ether covalent linkage is bound to a biological agent. Thesebiological agents are preferably DNA, RNA, siRNA, cDNA, proteins orimmunoglobulins. Also preferred are compounds where the silyl ethercovalent linkage is bound to a chemical agent. Useful chemical agentsinclude a pesticide, fungicide, insecticide, herbicide or biocide. Thesilicon atom of the silyl ether can further be covalently bound to alipid, polymer, ligand or tracer.

In another embodiment, the present subject matter is directed to amethod of treating a mammal, comprising administering a delivery vehicleas disclosed herein, wherein the compound comprises a pharmaceutical orbiological agent.

In another embodiment, the present subject matter is directed to amethod of modifying a property of an agent, comprising preparing a silylether covalently linked to the agent, wherein the agent is apharmaceutical, chemical or biological agent. In a preferred aspect ofthis embodiment, the silicon atom of the silyl ether is furthercovalently bound to a lipid, polymer, ligand or tracer. Preferably, theproperty modified by the present method is solubility in an aqueousmilieu Another preferred property modified by the present method is isstability. Yet, another preferred property modified by the presentmethod is is hydrophobicity.

In another embodiment, the present subject matter is directed to amethod of preparing a silyl ether compound, comprising contacting anucleophile with a silane, wherein a silyl ether compound is prepared.In this method, it is preferred that the nucleophile is selected fromthe group consisting of hydroxyl, amine, carboxyl and thiol. Preferably,the nucleophile is covalently linked to a pharmaceutical, chemical orbiological agent.

Preferred pharmaceutical agents include silyl ethers, esters, amines andthio ethers connected to, but not limited to, Camptothecin, Topotecan,Irinotecan, SN-38, Paclitaxel, Docetaxel Daunorubicin, Doxorubicin,Epirubicin, Idarubicin Gemcitabine, Cytarabine Brefeldin-A Imatinib,Gefitinib, Lapatinib, Sunitinib Methotrexate, Folinic Acid EffluxInhibitors, ATP-Binding Inhibitors Cytochrome-C, Ovalbumin siRNAAnti-Luciferase, siRNA Androgen Receptor, and RNA Replicon. Other agentsinclude Busulfan, Chlorambucil, Cyclophosphamide, melphalan, Carmustine,Lomustine, Cladribine, Cytarabine (Cytosine Arabinoside), Floxuridine(FUDR, 5-Fluorodeoxyuridine), Fludarabine, 5-Fluorouracil (5FU),Hydroxyurea, 6-Mercaptopurine (6 MP), Methotrexate (Amethopterin),6-Thioguanine, Pentostatin, Pibobroman, Tegafur, Trimetrexate,Glucuronate, 5-Fluorouracil (5-FU), Pemetrexed, Antitumor antibioticsincluding Aclarubicin, Bleomycin, Dactinomycin (Actinomycin D),Mitomycin C, Mitoxantrone, Plicamycin (Mithramycin), Mitotic inhibitorsinclude plant alkaloids and other natural agents that can inhibit eitherprotein synthesis required for cell division or mitosis, Docetaxel,Vinblastine sulfate, Vincristine, Etoposide (VP16), Carboplatin,cisplatin and oxaliplatin.

A combination drug or fixed-dose combination (FDC) is a formulation oftwo or more active ingredients combined in a single dosage form,available in certain fixed doses. Fixed-dose combination drug productsmay improve medication compliance by reducing the pill burden ofpatients, as well as any usual advantages of combination therapy.Multiple ABS pro-drugs, monomers and particles as described herein canbe co-encapsulated into a single particle or capsule, etc. orco-delivered in separate particles or capsules, etc. In either scenario,the drug release rates can be tuned as described herein to thetherapeutic indication by changing the subsituent group on the siliconatom. For example, delivery of a chemotherapeutic that induces DNAdamage, such as cisplatin along with a DNA repair-blocking drug such asa cdk-inhibitor therapy can improve the efficacy of thechemotherapeutic. In another example, the co-encapsulation orco-delivery of anti-nausea or pain medication with a chemotherapeuticcould provide benefits as the release of these drugs can be individuallytuned to release at the same time or at staggered times. Drug cocktailsof antiretrovirals are usually recommended for the treatment of AIDS.Below in Table 1 are some combinations of fixed dose combinations ofmultiple antiretroviral drugs combined into a single pill.

TABLE 1 FDC of Antiretrovirals Brand Drug Names Date of FDA Name (INN)Approval Company Combivir zidovudine + Sep. 26, 1997 GlaxoSmithKlinelamivudine Trizivir abacavir + Nov. 15, 2000 GlaxoSmithKlinezidovudine + lamivudine Kaletra lopinavir + Sep. 15, 2000 AbbottLaboratories ritonavir Epzicom abacavir + Aug. 2, 2004 GlaxoSmithKline(in USA) lamivudine Kivexa (in Europe) Truvada emtricitabine + Aug. 2,2004 Gilead Sciences tenofovir Atripla efavirenz + Jul. 12, 2006 GileadSciences and emtricitabine + Bristol-Myers tenofovir Squibb

Other therapeutic indications which may benefit from drug cocktailsinclude treatment of cancer, i.e., the combination of chemotherapy andpain/nausea medications, mental illness, cardiovascular disease, asthmaand arthritis; vaccines that contain antigen-adjuvants known in the artand protein-polysaccharides known in the art. In further embodiments thesubject matter disclosed herein can be utilized with the particles andcompositions disclosed in the following co-pending patent applicationpublications, each of which are incorporated herein by reference intheir entirety: US 2009/0028910; US 2009/0061152; WO 2007/024323; US2009/0220789; US 2007/0264481; US 2010;0028994; US 2010;0196277; WO2008/106503; US 2010/0151031; WO 2008/100304; WO 2009/041652;PCT/US2010/041797; US 2008/0181958; WO 2009/111588; and WO 2009/132206.

In some embodiments, the drug solubility is increased through thelinkage of the present invention. The linkage of the present inventionwill block or protect polar functional groups, such as for example, OH,NH₂, COO—, SH thereby making the drug attached thereto more hydrophobic.In some embodiments where it is not desired to make the drug morehydrophobic, the particle of the present invention can be configuredusing highly charged or polar monomers/polymers.

According to some embodiments of the present invention, the drugconcentration available at a target biologic system or location isincreased through use of the linkage of the present invention. Accordingto such embodiments, the present invention provides a system tocovalently attach a drug to a particle for controlled or protecteddelivery. Covalently attaching the drug to the surface or interior of aparticle, according to the present invention, eliminates diffusion ofthe drug out of or away from the particle. In some embodiments, bycovalently attaching the drug to the particle ensures that the amount ofdrug charged (concentration before particle fabrication) and the amountof drug encapsulated (concentration after particle fabrication) aresubstantially similar Typically, non-covalently encapsulated drugs canbe washed away from the particle leading to a considerable differencebetween the amount of drug charged and the amount of encapsulated drug.Moreover, due to the covalent nature of the silyl linkage, such linkagewill provide particle-drug stability that is greater than the affinitybinding (hydrogen bonding) found between avidin/biotin as a linker.

According to some embodiments of the present invention, utilizing thechlorosilane chemistry reaction with the particle and/or its cargo fordelivery to a target location provides a reaction that is fast, simpleand affordable. In some embodiments, the silane linkage can be tailoredto degrade at different rates based on i) the substituent on the siliconatom, ii) the degree of lipidization, or iii) the degree of surfacecross-linking. In further embodiments, the properties of a particle canbe changed from hydrophobic to hydrophilic or from slowly degrading torapidly degrading using identical reaction conditions and the chemistryis completely reversible and all modifications to the surface of theparticle or drug will eventually disappear. According to some aspects ofthe present invention, the chlorosilane chemistry is reactive with waterand therefore the reactions disclosed in the present invention should becarried out under anhydrous conditions and the particle used inassociation with the present invention need to be capable ofwithstanding anhydrous conditions.

In some embodiments, the present invention provides pro-drug linkagesthat are acid labile and degradable under in vivo conditions, such asfor example, inflammation tumor, endosomal, or lysosomal conditions, orthe like. In some embodiment, the reversible nature of the linkagesfacilitates releasing the linked cargo for treating or diagnosing atarget in vivo condition. Di-alkyl silane linkages are acid labile andcan degrade under conditions found in vivo (sights of inflammation,tumor tissue, endosomes in cells, and lysosomes in cells). Theselinkages can be utilized to alter the properties of ananoparticle/liposome ranging from lipophilic to hydrophilic. Due to thereversible nature of these linkages, once the particle has reached anarea of low acidity the properties of the particle can be completelyreversed.

In some embodiments, the polymer is “PEG” or “poly(ethylene glycol)” asused herein, is meant to encompass any water-soluble poly(ethyleneoxide). Typically, PEGs for use in the present invention will comprisethe following structure: “—(CH₂CH₂O)_(n)—”. The variable (n) is 3 to3,000, or about 3 to about 30,000; about 3 to about 10,000 or about 3 toabout 5,000. The terminal groups and architecture of the overall PEG mayvary. PEGs having a variety of molecular weights, structures orgeometries as is known in the art. “Water-soluble”, in the context of awater soluble polymer is any segment or polymer that is soluble in waterat room temperature. Typically, a water-soluble polymer or segment willtransmit at least about 75%, more preferably at least about 95% oflight, transmitted by the same solution after filtering. On a weightbasis, a water-soluble polymer or segment thereof will preferably be atleast about 35% (by weight) soluble in water, more preferably at leastabout 50% (by weight) soluble in water, still more preferably about 70%(by weight) soluble in water, and still more preferably about 85% (byweight) soluble in water. It is most preferred, however, that thewater-soluble polymer or segment is about 95% (by weight) soluble inwater or completely soluble in water.

An “end-capping” or “end-capped” group is an inert group present on aterminus of a polymer such as PEG. An end-capping group is one that doesnot readily undergo chemical transformation under typical syntheticreaction conditions. An end capping group is generally an alkoxy group,—OR, where R is an organic radical comprised of 1-20 carbons and ispreferably lower alkyl (e.g., methyl, ethyl) or benzyl. “R” may besaturated or unsaturated, and includes aryl, heteroaryl, cyclo,heterocyclo, and substituted forms of any of the foregoing. When thepolymer has an end-capping group comprising a detectable label, theamount or location of the polymer and/or the moiety (e.g., active agent)to which the polymer is coupled, can be determined by using a suitabledetector. Such labels include, without limitation, fluorescers,chemiluminescers, moieties used in enzyme labeling, calorimetric (e.g.,dyes), metal ions, radioactive moieties, and the like.

As used herein, the term “tracers” include, without limitation,fluorescers, chemiluminescers, moieties used in enzyme labeling,calorimetric (e.g., dyes), metal ions, radioactive moieties, and thelike.

Lipids include natural or synthetic triglycerides or mixtures of same,monoglycerides and diglycerides, alone or mixtures of same or with e.g.triglycerides, self-emulsifying modified lipids, natural and syntheticwaxes, fatty alcohols, including their esters and ethers and in the formof lipid peptides, or any mixtures of same.

Practice of the method of the present invention comprises administeringto a subject a therapeutically effective amount of a silyl ethercompound as described herein or a delivery vehicle containing such acompound.

Routes of administration for a therapeutically effective amount of asilyl ether composition or delivery vehicle include but are not limitedto intravenous or parenteral administration, oral administration,topical administration, transmucosal administration and transdermaladministration. For intravenous or parenteral administration, i.e.,injection or infusion, the composition may also contain suitablepharmaceutical diluents and carriers, such as water, saline, dextrosesolutions, fructose solutions, ethanol, or oils of animal, vegetative,or synthetic origin. It may also contain preservatives, and buffers asare known in the art. When a therapeutically effective amount isadministered by intravenous, cutaneous or subcutaneous injection, thesolution can also contain components to adjust pH, isotonicity,stability, and the like, all of which is within the skill in the art.The pharmaceutical composition of the present invention may also containstabilizers, preservatives, buffers, antioxidants, or other additiveknown to those of skill in the art. Typically, compositions forintravenous or parenteral administration comprise a suitable sterilesolvent, which may be an isotonic aqueous buffer or pharmaceuticallyacceptable organic solvent. The compositions can also include asolubilizing agent as is known in the art if necessary. Compositions forintravenous or parenteral administration can optionally include a localanesthetic to lessen pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form in a hermetically sealed container such as an ampoule orsachette. The pharmaceutical compositions for administration byinjection or infusion can be dispensed, for example, with an infusionbottle containing, for example, sterile pharmaceutical grade water orsaline. Where the pharmaceutical compositions are administered byinjection, an ampoule of sterile water for injection, saline, or othersolvent such as a pharmaceutically acceptable organic solvent can beprovided so that the ingredients can be mixed prior to administration.

The duration of intravenous therapy using the pharmaceutical compositionof the present invention will vary, depending on the condition beingtreated or ameliorated and the condition and potential idiosyncraticresponse of each individual mammal. The duration of each infusion isfrom about 1 minute to about 1 hour. The infusion can be repeated asnecessary.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection. Useful injectable preparations includesterile suspensions, solutions or emulsions of the active compound(s) inaqueous or oily vehicles. The compositions also can contain solubilizingagents, formulating agents, such as suspending, stabilizing and/ordispersing agent. The formulations for injection can be presented inunit dosage form, e.g., in ampules or in multidose containers, and cancontain added preservatives. For prophylactic administration, thecompound can be administered to a patient at risk of developing one ofthe previously described conditions or diseases. Alternatively,prophylactic administration can be applied to avoid the onset ofsymptoms in a patient suffering from or formally diagnosed with theunderlying condition.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, and the like. Determination of aneffective dosage is well within the capabilities of those skilled in theart coupled with the general and specific examples disclosed herein.

Oral administration of the composition or vehicle can be accomplishedusing dosage forms including but not limited to capsules, caplets,solutions, suspensions and/or syrups. Such dosage forms are preparedusing conventional methods known to those in the field of pharmaceuticalformulation and described in the pertinent texts, e.g., in Remington:The Science and Practice of Pharmacy (2000), supra.

The dosage form may be a capsule, in which case the activeagent-containing composition may be encapsulated in the form of aliquid. Suitable capsules may be either hard or soft, and are generallymade of gelatin, starch, or a cellulosic material, with gelatin capsulespreferred. Two-piece hard gelatin capsules are preferably sealed, suchas with gelatin bands or the like. See, for e.g., Remington: The Scienceand Practice of Pharmacy (2000), supra, which describes materials andmethods for preparing encapsulated pharmaceuticals.

Capsules may, if desired, be coated so as to provide for delayedrelease. Dosage forms with delayed release coatings may be manufacturedusing standard coating procedures and equipment. Such procedures areknown to those skilled in the art and described in the pertinent texts(see, for e.g., Remington: The Science and Practice of Pharmacy (2000),supra). Generally, after preparation of the capsule, a delayed releasecoating composition is applied using a coating pan, an airless spraytechnique, fluidized bed coating equipment, or the like. Delayed releasecoating compositions comprise a polymeric material, e.g., cellulosebutyrate phthalate, cellulose hydrogen phthalate, cellulose proprionatephthalate, polyvinyl acetate phthalate, cellulose acetate phthalate,cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulosesuccinate, carboxymethyl ethylcellulose, hydroxypropyl methylcelluloseacetate succinate, polymers and copolymers formed from acrylic acid,methacrylic acid, and/or esters thereof.

Sustained-release dosage forms provide for drug release over an extendedtime period, and may or may not be delayed release. Generally, as willbe appreciated by those of ordinary skill in the art, sustained-releasedosage forms are formulated by dispersing a drug within a matrix of agradually bioerodible (hydrolyzable) material such as an insolubleplastic, a hydrophilic polymer, or a fatty compound. Insoluble plasticmatrices may be comprised of, for example, polyvinyl chloride orpolyethylene. Hydrophilic polymers useful for providing a sustainedrelease coating or matrix cellulosic polymers include, withoutlimitation: cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetatephthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulosephthalate, hydroxypropylcellulose phthalate, cellulosehexahydrophthalate, cellulose acetate hexahydrophthalate, andcarboxymethylcellulose sodium; acrylic acid polymers and copolymers,preferably formed from acrylic acid, methacrylic acid, acrylic acidalkyl esters, methacrylic acid alkyl esters, and the like, e.g.copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethylacrylate, methyl methacrylate and/or ethyl methacrylate, with aterpolymer of ethyl acrylate, methyl methacrylate andtrimethylammonioethyl methacrylate chloride (sold under the tradenameEudragit RS) preferred; vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetatecrotonic acid copolymer, and ethylene-vinyl acetate copolymers; zein;and shellac, ammoniated shellac, shellac-acetyl alcohol, and shellacn-butyl stearate. Fatty compounds for use as a sustained release matrixmaterial include, but are not limited to, waxes generally (e.g.,carnauba wax) and glyceryl tristearate.

Topical administration of a silyl ether composition or delivery vehiclecan be accomplished using any formulation suitable for application tothe body surface, and may comprise, for example, an ointment, cream,gel, lotion, solution, paste or the like, and/or may be prepared so asto contain liposomes, micelles, and/or microspheres. Preferred topicalformulations herein are ointments, creams, and gels.

Ointments, as is well known in the art of pharmaceutical formulation,are semisolid preparations that are typically based on petrolatum orother petroleum derivatives. The specific ointment base to be used, aswill be appreciated by those skilled in the art, is one that willprovide for optimum drug delivery, and, preferably, will provide forother desired characteristics as well, e.g., emolliency or the like. Aswith other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing. As explained in Remington: TheScience and Practice of Pharmacy (2000), supra, ointment bases may begrouped in four classes: oleaginous bases; emulsifiable bases; emulsionbases; and water-soluble bases. Oleaginous ointment bases include, forexample, vegetable oils, fats obtained from animals, and semisolidhydrocarbons obtained from petroleum. Emulsifiable ointment bases, alsoknown as absorbent ointment bases, contain little or no water andinclude, for example, hydroxystearin sulfate, anhydrous lanolin andhydrophilic petrolatum. Emulsion ointment bases are either water-in-oil(W/O) emulsions or oil-in-water (O/W) emulsions, and include, forexample, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight (See, e.g., Remington: The Scienceand Practice of Pharmacy (2002), supra).

Creams, as also well known in the art, are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream bases arewater-washable, and contain an oil phase, an emulsifier and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceuticalformulation, gels-are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also,preferably, contain an alcohol and, optionally, an oil. Preferred“organic macromolecules,” i.e., gelling agents, are crosslinked acrylicacid polymers such as the “carbomer” family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCarbopol® trademark. Also preferred are hydrophilic polymers such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers andpolyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solubilizers may be used tosolubilize certain active agents. For those drugs having an unusuallylow rate of permeation through the skin or mucosal tissue, it may bedesirable to include a permeation enhancer in the formulation; suitableenhancers are as described elsewhere herein.

Transmucosal administration of a silyl ether composition or deliveryvehicle can be accomplished using any type of formulation or dosage unitsuitable for application to mucosal tissue. For example, a silyl ethercomposition or delivery vehicle may be administered to the buccal mucosain an adhesive patch, sublingually or lingually as a cream, ointment, orpaste, nasally as droplets or a nasal spray, or by inhalation of anaerosol formulation or a non-aerosol liquid formulation.

Preferred buccal dosage forms will typically comprise a therapeuticallyeffective amount of a silyl ether composition or delivery vehicle and abioerodible (hydrolyzable) polymeric carrier that may also serve toadhere the dosage form to the buccal mucosa. The buccal dosage unit isfabricated so as to erode over a predetermined time period, wherein drugdelivery is provided essentially throughout. The time period istypically in the range of from about 1 hour to about 72 hours. Preferredbuccal delivery preferably occurs over a time period of from about 2hours to about 24 hours. Buccal drug delivery for short-term use shouldpreferably occur over a time period of from about 2 hours to about 8hours, more preferably over a time period of from about 3 hours to about4 hours. As needed buccal drug delivery preferably will occur over atime period of from about 1 hour to about 12 hours, more preferably fromabout 2 hours to about 8 hours, most preferably from about 3 hours toabout 6 hours. Sustained buccal drug delivery will preferably occur overa time period of from about 6 hours to about 72 hours, more preferablyfrom about 12 hours to about 48 hours, most preferably from about 24hours to about 48 hours. Buccal drug delivery, as will be appreciated bythose skilled in the art, avoids the disadvantages encountered with oraldrug administration, e.g., slow absorption, degradation of the activeagent by fluids present in the gastrointestinal tract and/or first-passinactivation in the liver.

The “therapeutically effective amount” of a silyl ether composition ordelivery vehicle in the buccal dosage unit will of course depend on thepotency and the intended dosage, which, in turn, is dependent on theparticular individual undergoing treatment, the specific indication, andthe like. The buccal dosage unit will generally contain from about 1.0wt. % to about 60 wt. % active agent, preferably on the order of fromabout 1 wt. % to about 30 wt. % active agent. With regard to thebioerodible (hydrolyzable) polymeric carrier, it will be appreciatedthat virtually any such carrier can be used, so long as the desired drugrelease profile is not compromised, and the carrier is compatible with asilyl ether composition or delivery vehicle and any other components ofthe buccal dosage unit. Generally, the polymeric carrier comprises ahydrophilic (water-soluble and water-swellable) polymer that adheres tothe wet surface of the buccal mucosa. Examples of polymeric carriersuseful herein include acrylic acid polymers and co, e.g., those known as“carbomers” (Carbopol®, which may be obtained from B. F. Goodrich, isone such polymer). Other suitable polymers include, but are not limitedto: hydrolyzed polyvinylalcohol; polyethylene oxides (e.g., SentryPolyox® water soluble resins, available from Union Carbide);polyacrylates (e.g., Gantrez®, which may be obtained from GAF); vinylpolymers and copolymers; polyvinylpyrrolidone; dextran; guar gum;pectins; starches; and cellulosic polymers such as hydroxypropylmethylcellulose, (e.g., Methocel®, which may be obtained from the DowChemical Company), hydroxypropyl cellulose (e.g., Klucel®, which mayalso be obtained from Dow), hydroxypropyl cellulose ethers (see, e.g.,U.S. Pat. No. 4,704,285 to Alderman), hydroxyethyl cellulose,carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, cellulose acetate phthalate, celluloseacetate butyrate, and the like.

Other components may also be incorporated into the buccal dosage formsdescribed herein. The additional components include, but are not limitedto, disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. Examples of disintegrants that may be usedinclude, but are not limited to, cross-linked polyvinylpyrrolidones,such as crospovidone (e.g., Polyplasdone® XL, which may be obtained fromGAF), cross-linked carboxylic methylcelluloses, such as croscarmelose(e.g., Ac-di-sol®, which may be obtained from FMC), alginic acid, andsodium carboxymethyl starches (e.g., Explotab®, which may be obtainedfrom Edward Medell Co., Inc.), methylcellulose, agar bentonite andalginic acid. Suitable diluents are those which are generally useful inpharmaceutical formulations prepared using compression techniques, e.g.,dicalcium phosphate dihydrate (e.g., Di-Tab®, which may be obtained fromStauffer), sugars that have been processed by cocrystallization withdextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pak®,which may be obtained from Amstar), calcium phosphate, cellulose,kaolin, mannitol, sodium chloride, dry starch, powdered sugar and thelike. Binders, if used, are those that enhance adhesion. Examples ofsuch binders include, but are not limited to, starch, gelatin and sugarssuch as sucrose, dextrose, molasses, and lactose. Particularly preferredlubricants are stearates and stearic acid, and an optimal lubricant ismagnesium stearate.

Sublingual and lingual dosage forms include creams, ointments andpastes. The cream, ointment or paste for sublingual or lingual deliverycomprises a therapeutically effective amount of the selected activeagent and one or more conventional nontoxic carriers suitable forsublingual or lingual drug administration. The sublingual and lingualdosage forms of the present invention can be manufactured usingconventional processes. The sublingual and lingual dosage units arefabricated to disintegrate rapidly. The time period for completedisintegration of the dosage unit is typically in the range of fromabout 10 seconds to about 30 minutes, and optimally is less than 5minutes.

Other components may also be incorporated into the sublingual andlingual dosage forms described herein. The additional componentsinclude, but are not limited to binders, disintegrants, wetting agents,lubricants, and the like. Examples of binders that may be used includewater, ethanol, polyvinylpyrrolidone; starch solution gelatin solution,and the like. Suitable disintegrants include dry starch, calciumcarbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, lactose, and the like. Wetting agents,if used, include glycerin, starches, and the like. Particularlypreferred lubricants are stearates and polyethylene glycol. Additionalcomponents that may be incorporated into sublingual and lingual dosageforms are known, or will be apparent, to those skilled in this art (See,e.g., Remington: The Science and Practice of Pharmacy (2000), supra).

Other preferred compositions for sublingual administration include, forexample, a bioadhesive to retain a silyl ether composition or deliveryvehicle sublingually; a spray, paint, or swab applied to the tongue; orthe like. Increased residence time increases the likelihood that theadministered invention can be absorbed by the mucosal tissue.

Transdermal administration of a silyl ether composition or deliveryvehicle through the skin or mucosal tissue can be accomplished usingconventional transdermal drug delivery systems, wherein the agent iscontained within a laminated structure (typically referred to as atransdermal “patch”) that serves as a drug delivery device to be affixedto the skin.

Transdermal drug delivery may involve passive diffusion or it may befacilitated using electrotransport, e.g., iontophoresis. In a typicaltransdermal “patch,” the drug composition is contained in a layer, or“reservoir,” underlying an upper backing layer. The laminated structuremay contain a single reservoir, or it may contain multiple reservoirs.In one type of patch, referred to as a “monolithic” system, thereservoir is comprised of a polymeric matrix of a pharmaceuticallyacceptable contact adhesive material that serves to affix the system tothe skin during drug delivery. Examples of suitable skin contactadhesive materials include, but are not limited to, polyethylenes,polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and thelike. Alternatively, the drug-containing reservoir and skin contactadhesive are separate and distinct layers, with the adhesive underlyingthe reservoir which, in this case, may be either a polymeric matrix asdescribed above, or it may be a liquid or hydrogel reservoir, or maytake some other form.

The backing layer in these laminates, which serves as the upper surfaceof the device, functions as the primary structural element of thelaminated structure and provides the device with much of itsflexibility. The material selected for the backing material should beselected so that it is substantially impermeable to the active agent andany other materials that are present, the backing is preferably made ofa sheet or film of a flexible elastomeric material. Examples of polymersthat are suitable for the backing layer include polyethylene,polypropylene, polyesters, and the like.

During storage and prior to use, the laminated structure includes arelease liner. Immediately prior to use, this layer is removed from thedevice to expose the basal surface thereof, either the drug reservoir ora separate contact adhesive layer, so that the system may be affixed tothe skin. The release liner should be made from a drug/vehicleimpermeable material.

Transdermal drug delivery systems may in addition contain a skinpermeation enhancer. That is, because the inherent permeability of theskin to some drugs may be too low to allow therapeutic levels of thedrug to pass through a reasonably sized area of unbroken skin, it isnecessary to coadminister a skin permeation enhancer with such drugs.Suitable enhancers are well known in the art and include, for example,those enhancers listed below in transmucosal compositions.

Formulations can comprise one or more anesthetics. Patient discomfort orphlebitis and the like can be managed using anesthetic at the site ofinjection. If used, the anesthetic can be administered separately or asa component of the composition. One or more anesthetics, if present inthe composition, is selected from the group consisting of lignocaine,bupivacaine, dibucaine, procaine, chloroprocaine, prilocaine,mepivacaine, etidocaine, tetracaine, lidocaine and xylocaine, and salts,derivatives or mixtures thereof.

The present subject matter is further described herein by the followingnon-limiting examples which further illustrate the invention, and arenot intended, nor should they be interpreted to, limit the scope of theinvention.

EXAMPLES

1. Reversible Lipidization of Particles

Chlorosilane lipids are used to “lipidize” the surface of a particle orliposome. Chemical modification by lipidization could improve oralbioavailability, minimize enzymatic degradation of the particle and/orits cargo, alter the circulation profiles of the nanoparticles, alterthe biodistribution profile, alter the hydrophilic/hydrophobic characterof the drug/cargo and/or change the charge of the drug until theparticle or liposome contacts a pH range whereby the covalent Si linkeris cleaved and the parent cargo/drug becomes available. The reversiblenature of the attachment of the lipid allows for the loss of the lipidunder controlled conditions. Once the particle has reached the target,e.g., the tumor, tissue, organ, cell of interest, etc., the lipid can becleaved under slightly acidic conditions, that allows for betteraccessibility and easier release of the drug. In preferred embodiments,a drug as described elsewhere herein is incorporated in the particle bya manner as described fully herein. Scheme 1 depicts a general syntheticroute to prepare particles, nanoparticles or liposomes and a list ofcommercially available lipids.

2. Reversible PEGylation of Nanoparticles

Chlorosilane poly(ethylene glycol) moieties are used to “PEGylate” thesurface of a nanoparticle or liposome. Chemical modification byPEGylation can improve water solubility, circulation in vivo, and thestealth properties of the particle. The reversible nature of theattachment of the PEG allows for the cleavage of the PEG residue underdesired conditions. For example, once the particle has reached thetumor, tissue, organ, cell of interest, etc. the PEG can be cleavedunder slightly acidic conditions. This allows for improved accessibilityto the particle and desired release of of cargo. The properties of thereversible bonds are tunable as described elsewhere herein. Scheme 2depicts a general synthetic route to prepare particles, nanoparticles orliposomes and a list of commercially available lipids.

3. Reversible PEGylation of Nanoparticles

Chlorosilane agents, which can be a pharmaceutical drug, biological orchemical agent, are used to coat the surface of a particle, nanoparticleor liposome with a payload of the agent(s). The agent is attached by areversible silyl ether, ester, amine or thio ether linkage, which can bedegraded, for example, in vivo. This chemical derivation can modify drugsolubility, circulation and ensure a large concentration reaches thedesired tissue. Sheme 3 depicts a general synthetic route to prepare thenanoparticles.

4. Surface Modification with a Reversibly Attached Targeting Ligand

In an embodiment, a targeting ligand can also be reversibly attached toa nanoparticle through the ABS monomer system of the present invention.The targing ligand can direct the particle and drug to the cell ortissue of interest. Once the particle reaches the cell and isinternalized, the targeting ligand can be cleaved allowing for betteraccessibility to the particle and easier release of the drug.

5. Methods of Preparing Reversible Asymmetric Silyl Ether Pro-drugs andBiologics

A polymerizable chlorosilane is used to incorporate therapeutics withinthe interior of a nanoparticle or liposome. The therapeutic can be i) adrug/chemotherapeutic, ii) a protein, iii) a peptide, or iv) a nucleicacid (DNA, RNA, siRNA). The therapeutic is attached by a reversiblesilyl ether linkage, which can be degraded in vivo. This chemicalmodification can provide improved solubility and biodistibution to atargeted area or tissue. Additionally, having the drug inside theparticle provides protection, which minimizes untimely degradation. Thefollowing structure II is an example of compounds described herein:

wherein “X” represents a pharmaceutical, chemical or biological agent.The following schemes depict synthetic routes for the preparation of theabove compounds. The selection of the alkyl substituent, R (e.g. methyl,ethyl, isopropyl, phenyl, or tert-butyl) on the Si atom can providetunable rates of degradation. For example, a relatively bulky tert-butylsubstituent leads to a more stable, less-degradable linkage. However,when a methyl or ethyl substituent was bound to the Si atom, the rate ofacid catalyzed hydrolysis increases by orders of magnitude.

6. Syntheses of ABS of Camptothecin-Silyl Ether Acrylate

a. Diethyl ABS of Camptothecin (Et-CPT)

i. Method 1

To a flame-dried round-bottom flask equipped with a magnetic stir bar(under inert atmosphere), camptothecin (CPT) (0.250 g, 0.718 mmol) wassuspended in 10 mL of dimethylformamide (DMF). Dimethylaminopyridine(DMAP) (0.090 g, 0.718 mmol, 1 eq.) and imidazole (0.342 g, 5.02 mmol, 7eq.) were added to the suspension. After 10 minutes, dichlorodiethylsilane (0.338 g, 2.15 mmol, 3 eq.) was added to the suspension andallowed to react for 72 hours. Throughout the course of the reaction theheterogeneous suspension completely dissolves into the DMF solvent.Hydroxyethyl Acrylate (HEA) (0.429 g, 3.59 mmol, 5 eq.) was added andallowed to react for an additional 12 hours. The reaction solution wasdissolve in 100 mL of ethyl acetate and washed with 3×50 mL of saturatedsodium chloride to remove the DMF. The ethyl acetate was removed byrotary evaporation in vacuo and the product was isolated by flashchromatography using 1:1 dichloromethane:ethyl acetate as eluent. Yield:43 mg (11%), yellow oil. ¹H NMR (400 MHz, CDCl₃):δ=0.80 (m, 4H), 1.00(m, 9H), 1.95 (quart., 2H), 4.08 (t, 2H), 4.32 (t, 2H), 5.30 (m, 3H),5.75 (m, 2H), 6.13 (dd, 1H), 6.38 (d, 1H), 7.62 (s, 1H), 7.65 (t, 1H),7.93 (t, 1H), 8.27 (d, 1H), 8.40 (s, 1H). HR-MS (m/z) calcd forC₂₉H₃₂N₂O₇Si, [M]⁺=548.1979, [M+Na]³⁰ =571.1876; found [M+Na]⁺m/z=571.1821.

ii. Method 2

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with argon), camptothecin (501 mg, 1.44 mmols), imidazole (684mg, 10.05 mmols) and 4-DMAP (182 mg, 1.49 mmols) were dissolved inanhydrous DMF (13 mL) to form a heterogeneous mixture. A clear reactionmixture was achieved after dichlorodiethyl-silane (0.6 mL, 4.05 mmols)was added and allowed to react for 30 minutes. After 92 hourshydroxyethyl acrylate (1 mL, 9.56 mmols) was added and stirred for anadditional 90 minutes. The reaction mixture was diluted with ethylacetate (150 mL) and washed with saturated NaCl (150 mL) to remove theDMF. The organic layer was removed by rotary evaporation in vacuo, andthe product was isolated by column chromatography. The product waseluted using a mixture of dichloromethane and ethyl acetate (8:2). Anyresidual solvent was removed in vacuo to yield an off-white liquid, 165mg (0.30 mmols, 20.8%). ¹H-NMR (600 MHz, CDCl₃):δ=0.71 (m, 2H, J=7.8Hz), 0.84 (m, 2H, J=7.8 Hz), 0.94-1.07 (m, 6H, J=7.8 Hz), 4.10 (m, 2H),4.31 (m, 2H), 5.33 (s, 2H), 5.40 (d, 1H, J=16.2 Hz), 5.56 (d, 1H, J=16.2Hz), 5.80 (dd, 1H, J=1.8 Hz, J=10.2 Hz), 6.14 (dd, 1H, J=10.2 Hz, J=17.4Hz), 6.32 (dd, 1H, J=1.8 Hz, J=17.4 Hz), 7.52 (s, 1H), 7.72 (t, 1H,J=7.2 Hz), 7.88 (t, 1H, J=7.2 Hz), 7.96 (s, 2H), 8.11 (d, 1H, J=7.8 Hz),8.22 (d, 1H, J=8.4 Hz), 8.68 (s, 1H). MS (m/z) calcd for C₂₉H₃₂N₂O₇Si,[M]⁺=548.1979, [M+Na]⁺⁼571.1877, [M+Cs]⁺=681.1033; found [M+Na]⁺m/z=571.1862, [M+Cs]⁺=783.1003.

b. Synthesis of Dimethyl ABS of Camptothecin (Me-CPT)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with N₂), camptothecin (0.500 g, 1.43 mmol), 4-dimethylaminopyridine (4- DMAP) (0.175 g, 1.43 mmol) and imidazole(0.681 g, 10.01 mmol) were dissolved in anhydrous DMF (12 mL) to form aheterogeneous mixture. A clear reaction mixture was achieved afterdichlorodimethyl silane (0.553 g, 4.29 mmol) was added and allowed toreact for 30 minutes. After 3.5 h hydroxyethyl acrylate (HEA) (0.830 g,7.15 mmol) was added and stirred for an additional 2 h. The reactionmixture was diluted with ethyl acetate (150 mL) and washed withsaturated NaCl (150 mL) to remove the DMF. The organic layer was removedby rotary evaporation in vacuo, and the product was isolated by columnchromatography. The product was eluted using a mixture of hexanes, ethylacetate and methanol (7:2:1). The resulting solid was dried in vacuo.Yield: 107.6 mg (14.4%), yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ=0.067(s, 3H), 0.27 (s, 3H), 0.90 (t, 3H, J=7.0 Hz), 1.93 (m, 2H), 3.99 (s,2H), 4.28 (s, 2H), 5.29 (s, 2H), 5.49 (s, 2H), 5.85 (d, 1H, J=10.2 Hz),6.16 (dd, 1H, J=10.28 Hz, 17.24 Hz), 6.28 (d, 1H, J=17.32 Hz), 7.37 (s,1H), 7.71 (t, 1H, J=7.4 Hz), 7.86 (t, 1H, J=8.0 Hz), 8.14 (t, 2H, J=9.48Hz), 8.69 (s, 1H). ¹³C NMR (150 MHz CDCl₃):δ=−0.680, −0.577, 8.060,32.686, 50.183, 61.164, 65.895, 66.241, 76.291, 98.307, 118.988,128.142, 128.212, 128.260, 128.537, 128.625, 130.019, 130.739, 130.916,131.221, 146.222, 149.019, 151.146, 152.517, 157.728, 166.359, 172.052.HR-MS (m/z) calcd for C₂₇H₂₈N₂O₇Si, [M]⁺=520.1666, [M+Na]⁺=543.1566,[M+Cs]⁺=653.0766; found [M+Cs]⁺=653.0720+2.8 ppm.

c. Synthesis of Diisopropyl ABS of Camptothecin (iPr—CPT)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with argon), camptothecin (250 mg, 0.718 mmols), imidazole (342mg, 5.02 mmols) and 4-DMAP (90 mg, 0.737 mmols) were dissolved inanhydrous DMF (8 mL) to form a heterogeneous mixture. A clear reactionmixture was achieved after dichlorodiisopropyl silane (0.4 mL, 2.22mmols) was added and allowed to react for 30 minutes. After 92 hourshydroxyethyl acrylate (1 mL, 9.56 mmols) was added and stirred for anadditional 90 minutes. The reaction mixture was diluted with ethylacetate (100 mL) and washed with saturated NaCl (100 mL) to remove theDMF. The organic layer was removed by rotary evaporation in vacuo, andthe product was isolated by column chromatography. The product waseluted using a mixture of dichloromethane and ethyl acetate (1:1). Anyresidual solvent was removed in vacuo to yield an off-white liquid, 118mg (0.21 mmols, 29.3%). ¹H-NMR (600 MHz, CDCl₃):δ=0.90-1.40 (m, 14H),1.95-2.15 (m, 2H), 4.13 (m, 2H), 4.33 (m, 2H), 5.32 (s, 2H), 5.70 (d,1H, J=25.2 Hz), 5.77 (dd, 1H, J=1.8 Hz, J=15.6 Hz), 6.11 (dd, 1H, J=15.6Hz, J=26.4 Hz), 6.38 (dd, 1H, J=1.8 Hz, J=26.4 Hz), 7.67 (m, 2H), 7.83(t, 1H, J=10.8 Hz), 7.94 (d, 1H, J=12 Hz), 8.26 (d, 1H, J=13.2 Hz), 8.40(s, 1H). MS (m/z) calcd for C₃₁H₃₆N₂O₇Si, [M]⁺=576.2292,[M+H]⁺=577.2370, [M+Na]⁺=599.2189, [M+Cs]⁺=709.1346; found[M+H]⁺=577.2362, [M+Na]⁺=599.2207, [M+Cs]⁺=709.1329.

d. Synthesis of Diphenyl ABS of Camptothecin (Ph-CPT)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with argon), camptothecin (500 mg, 1.44 mmols), imidazole (684mg, 10.05 mmols) and 4-DMAP (180 mg, 1.47 mmols) were dissolved inanhydrous DMF (15 mL) to form a heterogeneous mixture. A clear reactionmixture was achieved after dichlorodiphenyl silane (1.0 mL, 4.74 mmols)was added and allowed to react for 45 minutes. After 92 hourshydroxyethyl acrylate (1 mL, 9.56 mmols) was added and stirred for anadditional 60 minutes. The reaction mixture was diluted with ethylacetate (150 mL) and washed with saturated NaCl (150 mL) to remove theDMF. The organic layer was removed by rotary evaporation in vacuo, andthe product was isolated by column chromatography. The product waseluted using a mixture of dichloromethane and ethyl acetate (8:2). Anyresidual solvent was removed in vacuo to yield a pale yellow solid, 178mg (0.28 mmols, 19.4%). ¹H-NMR (600 MHz, CDCl₃):δ=1.01 (t, 3H),2.08-2.30 (m, 2H), 4.12 (br, 2H), 4.37 (br, 2H), 5.26 (m, 3H), 5.47 (d,1H, J=16.8 Hz), 5.77 (d, 1H, J=10.2 Hz), 6.07 (m, 1H), 6.35 (d, 1H,J=17.4 Hz), 7.30-7.50 (m, 4H), 7.57 (s, 1H), 7.70 (br, 5H), 7.87 (t, 1H,J=7.2 Hz), 7.97 (d, 1H, J=7.8 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.40 (s, 1H).MS (m/z) calcd for C₃₇H₃₂N₂O₇Si, [M]⁺=644.1979, [M+Na]⁺=667.1876,[M+Cs]⁺=777.1033; found [M+Cs]⁺=777.1141.

According to some embodiments, reversible linkages based ondialkylchloro silanes are used to change the intrinsic characteristicsof nanoparticles and liposomes. Each chlorosilane was investigated usingparticles fabricated from the Particle Replication In Non-wettingTemplates (PRINT) process.

7. Additional ABS of Alkaloids—Silyl Ether Quinoline Alkaloids

Scheme 6 depicts Topotecan and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure III:

Scheme 7 depicts Irinotecan and a preferred attachment:

Scheme 8 depicts SN-38 and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure IV:

8. ABS of Taxanes—Silyl Ether Taxanes

Scheme 9 depicts paclitaxel and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure:

Scheme 10 depicts Docetaxel and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure V:

9. ABS of Anthracyclines—Silyl Ether Anthracyclines

Scheme 11 depicts Daunorubicin and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure VI:

Scheme 12 depicts Doxorubicin and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure VII:

Scheme 13 depicts Epirubicin and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure VIII:

Scheme 14 depicts Idarubicin and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure IX:

10. ABS of Nucleosides—Silyl Ether Nucleosides

Scheme 16 depicts Gemcitabine and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure X′:

Scheme 17 depicts Cytarabine and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure XI:

a. Diethyl ABS of Gemcitabine (Et-GEM)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with argon), gemcitabine hydrochloride (500 mg, 1.67 mmols),imidazole (264 mg, 3.88 mmols) and 4-DMAP (204 mg, 1.67 mmols) weredissolved in anhydrous DMF (15 mL). After 15 minutes dichlorodiethylsilane (0.2 mL, 1.35 mmols) was added and allowed to react. After 60minutes hydroxyethyl acrylate (1 mL, 9.56 mmols) was added and stirredfor an additional 30 minutes. The reaction mixture was diluted withethyl acetate (150 mL) and washed with saturated NaCl (150 mL) to removethe DMF. The organic layer was removed by rotary evaporation in vacuo,and the product was isolated by column chromatography. The product waseluted using a mixture of dichloromethane and methanol (9:1). Anyresidual solvent was removed in vacuo to yield a clear and colorlessliquid (1° isomer) with a yield of 282 mg (0.61 mmols, 38.4%). ¹H-NMR(600 MHz, CDCl₃):δ=0.66 (m, 4H, J=7.8 Hz), 0.96 (t, 6H, J=7.8 Hz),1.50-2.30 (br, 1H), 3.90-4.18 (m, 5H), 4.20-4.40 (m, 3H), 5.80-5.90 (m,2H), 6.10-6.20 (dd, 1H, J=10.2 Hz, J=17.4 Hz), 6.31 (t, 1H, J=7.2 Hz),6.42 (dd, 1H, J=1.2 Hz, J=17.4 Hz), 7.70 (d, 1H, J=7.8 Hz). ¹³C-NMR (150MHz, CDCl₃):δ=3.67, 6.35, 6.36, 50.98, 60.35, 60.93, 61.37, 65.70,66.36, 69.31 (t, CF₂ coupling, J_(C—F)=22.5 Hz), 80.75, 84.31 (m, CF₂coupling), 95.55, 122.52 (t, CF₂ coupling, J_(C—F)=258 Hz), 128.18,131.57, 131.66, 140.93, 156.01, 165.92, 166.68. MS (m/z) calcd forC₁₈H₂₇F₂N₃O₇Si, [M]⁺=463.1586, [M +Na]⁺=486.1484, [M+Cs]⁺=596.0641;found [M+Na]⁺ m/z=486.1483, [M+Cs]⁺=596.0662.

Additionally, the 2° isomer was also isolated as a foamy semi-solid, 195mg (0.42 mmols, 26.5%). ¹H-NMR (600 MHz, CDCl₃):δ=0.69 (q, 4H, J=7.8Hz), 0.98 (t, 6H, J =7.8 Hz), 1.50-2.20 (br, 3H), 3.80 (dd, 1H, J=2.4Hz, 12.6 Hz), 3.91 (d, 1H, J=8.4 Hz), 3.95 (t, 2H, J=4.8 Hz), 4.04 (d,1H, J=12 Hz), 4.22-4.30 (m, 2H, J=6.6 Hz, 4.8 Hz), 4.43-4.63 (br, 1H),5.85 (dd, 2H, J=1.2 Hz, 10.8 Hz), 6.05-6.35 (br and dd, 2H, J=10.2 Hz,J=17.4 Hz), 6.42 (dd, 1H, J=1.2 Hz, 17.4 Hz), 7.10-7.50 (br, 1H), 7.58(d, 1H, J=7.2 Hz). ¹³C-NMR (150 MHz, CDCl₃):δ=3.82, 3.89, 6.11, 6.14,59.38, 61.01, 65.55, 69.76 (t, CF₂ coupling, J_(C—F)=22.5 Hz), 81.06,84.90 (m, CF₂ coupling), 96.34, 122.31 (t, CF₂ coupling, J_(C—F)=258Hz), 128.24, 131.40, 141.13, 156.18, 166.22, 166.46. MS (m/z) calcd forC₁₈H₂₇F₂N₃O₇Si, [M]⁺=463.1586, [M+Na]⁺=486.1484, [M+Cs]⁺=596.0641; found[M+Na]⁺ m/z=486.1467, [M+Cs]⁺=596.0649.

b. Diisopropyl ABS of Gemcitabine (iPr-GEM)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with argon), gemcitabine hydrochloride (507 mg, 1.69 mmols),imidazole (271 mg, 3.98 mmols) and 4-DMAP (209 mg, 1.71 mmols) weredissolved in anhydrous DMF (13 mL). After 15 minutes dichlorodiisopropylsilane (0.25 mL, 1.39 mmols) was added and allowed to react. After 135minutes hydroxyethyl acrylate (1 mL, 9.56 mmols) was added and stirredfor an additional 60 minutes. The reaction mixture was diluted withethyl acetate (150 mL) and washed with saturated NaCl (150 mL) to removethe DMF. The organic layer was removed by rotary evaporation in vacuo,and the product was isolated by column chromatography. The product waseluted using a mixture of dichloromethane and methanol (9:1). Anyresidual solvent was removed in vacuo to yield a white solid (1° isomer)with a yield of 260 mg (0.53 mmols, 33%). ¹H-NMR (600 MHz, CDCl₃):δ=1.05(d, 14H, J=2.4 Hz), 3.99 (t, 2H, J=4.8 Hz), 4.01-4.45 (m, 6H), 4.70-5.60(br, 1H), 5.85 (m, 2H), 6.15 (dd, 1H, J=10.8 Hz, J=17.4 Hz), 6.26 (br,1H), 6.35 (t, 1H, J=7.8 Hz), 6.42 (dd, 1H, J=1.2 Hz, J=17.4 Hz), 7.64(d, 1H, J=7.2 Hz), 7.86 (br, 1H). ¹³C-NMR (150 MHz, CDCl₃):δ=11.85,11.92, 17.11, 17.13, 17.17, 60.61, 61.10, 61.14, 65.53, 65.57, 66.49,69.41 (t, CF₂ coupling, J_(C—F)=22.5 Hz), 72.89, 80.84, 84.02 (q, CF₂coupling, J_(C—F) =24 Hz, 36 Hz), 95.50 (d, J=6 Hz), 96.26, 122.37 (t,CF₂ coupling, J_(C—F)=258 Hz), 128.10, 131.47, 139.92 (br, CF₂coupling), 140.80, 155.51, 155.86, 165.82, 166.55. MS (m/z) calcd forC₂₀H₃₁F₂N₃O₇Si, [M]⁺=491.1899, [M+Na]⁺=514.1797, [M+Cs]⁺=624.0954; found[M+Na]⁺ m/z=514.1765, [M+Cs]⁺=624.0959.

Additionally, the 2° isomer was also isolated as a clear oil, 193 mg(0.39 mmols, 24.3%). ¹H-NMR (600 MHz, CDCl₃):δ=1.03 (s, 14H), 3.79 (d,1H, J=10.8 Hz), 3.88 (d, 1H, J=7.8 Hz), 4.00 (t, 2H, J=4.8 Hz), 4.05 (d,1H, J=12.6 Hz), 4.27 (m, 2H, J =5.4 Hz, J=6.6 Hz), 4.51 (br, 2H), 5.85(t, 2H, J=9.6 Hz, 7.2 Hz), 6.12 (dd, 1H, J=10.5 Hz, J=17.4 Hz), 6.22(br, 1H), 6.41 (d, 1H, J=17.4 Hz), 6.80 (br, 1H), 7.53 (d, 1H, J=7.8Hz), 7.90 (br, 1H). ¹³C-NMR (150 MHz, CDCl₃):δ=11.87, 11.99, 16.70,16.80, 16.85, 16.88, 50.67 (p, J=7.5 Hz, J=3 Hz), 59.37, 61.27, 65.39,69.79 (t, CF₂ coupling, J_(C—F)=22.5 Hz), 81.21, 84.90 (br, CF₂coupling), 96.12, 122.15 (t, CF₂ coupling, J_(C—F)=258 Hz), 128.04,131.34, 141.01, 155.97, 165.97, 166.37. MS (m/z) calcd forC₂₀H₃₁F₂N₃O₇Si, [M]⁺=491.1899, [M+Na]⁺=514.1797, [+Cs]⁺=624.0954; found[M+Na]⁺ m/z=514.1780, [M+Cs]⁺=624.0894.

c. Di-tert-butyl ABS of Gemcitabine (tBu-GEM)

To a 50 mL round bottom flask equipped with a magnetic stir bar (purgedwith argon) di-tert-butylsilyl bis(trifluoromethanesulfonate) (0.84 g,1.90 mmol) was dissolved in anhydrous DMF (12 mL) and anhydrous pyridine(1 mL) and cooled in an ice bath. Hydroxyethyl acrylate (0.22 g, 1.90mmol) was diluted in 6 mL of anhydrous DMF and added to the reaction ina drop wise fashion over one hour. The reaction was allowed to stir andwarm to room temperature for 2 hours after which gemcitabine (0.50 g,1.90 mmol) was added and allowed to react overnight. The reactionmixture was diluted with ethyl acetate (150 mL) and washed withsaturated NaCl (150 mL) to remove the DMF. The organic layer was removedby rotary evaporation in vacuo, and the product was isolated by columnchromatography. The product was eluted using a mixture ofdichloromethane and methanol (92:8 ratio). Any residual solvent wasremoved in vacuo and gave colourless foam with a yield of 192 mg (0.37mmol, 20%). ¹H-NMR (400 MHz, CDCl₃):δ=1.00 (d, 18H, J=2.0 Hz), 4.00-4.23(m, 5H), 4.23-4.37 (m, 3H), 5.84 (d, 1H, J=10.4 Hz), 5.89 (d, 1H, J=7.6Hz), 6.10 (dd, 1H, J=10.4 Hz, 17.4 Hz), 6.27 (t, 1H, J=8.0 Hz), 6.39(dd, 1H, J=1.6 Hz, 17.4 Hz), 7.54 (d, 1H, J=7.2 Hz). ¹³C-NMR (150 MHz,CDCl₃):δ=21.27, 21.33, 27.81, 27.87, 61.85, 62.22, 65.87, 69.90 (dd,J_(CF)=18.0 Hz, 27.0 Hz), 81.51, 83.99 (m), 96.20, 119.35, 120.67,122.40, 124.12, 128.28, 131.69, 141.04, 155.90, 165.36, 166.78. MS (m/z)calcd for C₂₂H₃₅F₂N₃O₇Si, [M]⁺=519.2212, [M+Na]⁺=542.2110,[M+Cs]⁺=652.1267; found [+Na]⁺ m/z=542.17, [M+Cs]⁺=652.08.

11. Silyl Ether Brefeldin-A

Scheme 18 depicts ABS Brefeldin-A and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure XII:

12. Silyl Ether Tyrosine Kinase Inhibitors

Scheme 19 depicts Cytarabine and a preferred attachment:

Scheme 20 depicts Gefitinib and a preferred attachment:

Scheme 21 depicts Lapatinib and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure XIII:

Scheme 22 depicts Sunitinib and a preferred attachment:

13. Silyl Ether Antifolates

Scheme 23 depicts Methotrexate and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure XIV:

Scheme 24 depicts Folinic Acid and a preferred attachment:

However, other potential sights of silane attachment are denoted with Xin the following structure XV:

14. Silyl Ether Proteins

Scheme 25 depicts Ctochrome C, Ovalbumin, etc. and a preferredattachment at side group:

FIG. 1 depicts exemplary amino acid residues that can provide a sight ofsilane attachment.

15. Silyl Ether Nucleic Acids

Silyl ether nucleic acids such as RNA, siRNA, RNA Replicon, etc. can beprepared. Scheme 26 depicts a synthetic route via functionalization ofthe hydroxyls on the side of the RNA chain.

Scheme 27 depicts a synthetic route via functionalization of thehydroxyls on the end of the RNA chain.

16. ABS of Dasatinab

a. Diethyl ABS of Dasatinab (Et-DAS)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with N2), dasatinib (0.500 g, 1.024 mmol, 1.0 eq.),4-dimethylaminopyridine (4-DMAP) (0.1245 g, 1.019 mmol, 1.0 eq.) andimidazole (0.4860 g, 7.139 mmol, 7.0 eq.) were dissolved in 12 mL ofanhydrous DMF. After 30 minutes dichlorodiethyl silane (0.4807 g, 3.059mmol, 3.0 eq.) was added to the mixture. After 2.5 hours hydroxyethylacrylate (0.592 g, 5.098 mmol, 5.0 eq.) was added and allowed to reactfor an additional 1 hour.

The reaction mixture was diluted with ethyl acetate (150 mL) and washedwith saturated NaCl (150 mL) to remove the DMF. The organic layer wasremoved by rotary evaporation in vacuo, and the product was isolated bycolumn chromatography. The product was eluted using a mixture ofhexanes, ethyl acetate and methanol (7:2:1). The resulting solid wasdried in vacuo. Yield: 122.1 mg (17.3%), white solid. ¹H NMR (400 MHz,DMSO-d₆):δ=0.58 (q, 4H, J=8.04 Hz), 0.91 (t, 6H, J=7.88 Hz), 2.23 (s,3H), 2.40 (s, 3H), 2.62* (m, 6H), 3.44 (s, 1H), 3.49 (s, 4H), 3.78 (t,2H, J=6.0 Hz), 3.90 (m, 2H), 4.20 (m, 2H), 5.96 (dd, 1H, J=1.56 Hz,10.28 Hz), 6.04 (s, 1H), 6.19 (dd, 1H, J=10.32 Hz, 17.26 Hz), 6.34 (dd,1H, J=1.56 Hz, 17.26 Hz), 7.28 (m, 2H), 7.39 (m, 1H), 8.21 (s, 1H), 9.87(s, 1H), 11.46 (s, 1H). ¹³C NMR (150 MHz DMSO-d₆):δ=3.041, 3.315, 6.383,6.449, 18.371, 25.640, 43.639, 49.844, 52.819, 59.777, 59.817, 59.997,60.313, 65.442, 82.701, 125.703, 127.060, 128.216, 128.248, 129.074,131.765, 132.477, 133.568, 138.868, 140.887, 157.016, 159.976, 162.410,162.651, 165.195, 165.523. HR-MS (m/z) calcd for C₃₁H₄₂ClN₇O₅SSi,[M]⁺=687.2426, [M+H]⁺=688.2426, [M+Cs]⁺=820.1480; found [M+H]⁺m/z=688.2504+5.9 ppm, [M+Cs]+=820.1480+5.3 ppm. (*Determined usingMeOD-d₄)

b. Diisopropyl ABS of Dasatinib (iPr-DAS)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with N₂), dasatinib (0.500 g, 1.024 mmol, 1.0 eq.),4-dimethylaminopyridine (4-DMAP) (0.124 g, 1.014 mmol, 1.0 eq.) andimidazole (0.486 g, 7.139 mmol, 7.0 eq.) were dissolved in 15 mL ofanhydrous DMF. After 15 minutes, dichlorodiisopropyl silane (0.568 g,3.067 mmol, 3.0 eq.) was added to the mixture. After 45 minuteshydroxyethyl acrylate (HEA) (0.594 g, 5.11 mmol, 5.0 eq.) was added andallowed to react for an additional 45 minutes. The reaction mixture wasdiluted with ethyl acetate (150 mL) and washed with saturated NaCl (150mL) to remove the DMF. The organic layer was removed by rotaryevaporation in vacuo, and the product was isolated by columnchromatography. The product was eluted using a mixture of hexanes, ethylacetate and methanol (7:2:1). The resulting solid was dried in vacuo.Yield: 161.8 mg (22.1%), white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=0.99(s, 14H), 2.23 (s, 3H), 2.40 (s, 3H), 2.65*(m, 6H), 3.49 (s, 4H), 3.84(t, 2H, J=6.04 Hz), 3.96 (m, 2H), 4.23 (m, 2H), 5.96 (dd, 1H, J=1.6 Hz,10.28 Hz), 6.04 (s, 1H), 6.18 (dd, 1H, J=10.28 Hz, 17.34 Hz), 6.34 (dd,1H, J=1.6 Hz, 17.28 Hz), 7.27 (m, 2H), 7.39 (m, 1H), 8.21 (s, 1H), 9.87(s, 1H), 11.46 (s, 1H). ¹³C NMR (150 MHz DMSO-d₆):δ=11.397, 17.132,17.137, 18.317, 25.592, 43.641, 52.837, 59.755, 60.643, 60.703, 65.341,82.645, 125.701, 127.023, 128.131, 128.244, 129.042, 131.666, 132.440,133.521, 138.830, 140.830, 156.952, 159.924, 162.388, 162.564, 165.178,165.477. HR-MS (m/z) calcd for C₃₃H₄₆C₁N₇O₅SSi, [M]⁺=715.2739,[M+Na]⁺=738.2636; found [M+Na]⁺ m/z=738.2637+2.8 ppm,[M+Cs]⁺=848.1793+4.9 ppm. (*Determined using MeOD-d₄)

c. Di-tertbutyl ABS of Dasatinib (tBu-DAS)

In a dry 20 mL scintillation vial equipped with a magnetic stir bar(purged with N₂), dasatinib (0.500 g, 1.024 mmol, 1.0 eq.),4-dimethylaminopyridine (4-DMAP) (0.1245 g, 1.019 mmol, 1.0 eq.) andimidazole (0.4860 g, 7.139 mmol, 7.0 eq.) were dissolved in 12 mL ofanhydrous DMF. After 10 minutes,ditertbutylsilylbis(trifluoromethanesulfonate) (1.34 g, 3.042 mmol, 3.0eq.) was added to the mixture. After 45 minutes hydroxyethyl acrylate(HEA) (0.592 g, 5.095 mmol, 5 eq.) was added and allowed to react for anadditional 45 minutes. The reaction mixture was diluted with ethylacetate (150 mL) and washed with saturated NaCl (150 mL) to remove theDMF. The organic layer was removed by rotary evaporation in vacuo, andthe product was isolated by column chromatography. The product waseluted using a mixture of hexanes, ethyl acetate and methanol (7:2:1).The resulting solid was dried in vacuo. Yield: 167.1 mg (22%), whitesolid. ¹H NMR (400 MHz, DMSO-d₆):δ=0.97 (s, 18H), 2.23 (s, 3H), 2.40 (s,3H), 2.66*(m, 6H), 3.49 (s, 4H), 3.94 (t, 2H, J=5.96 Hz), 4.05 (m, 2H),4.24 (m, 2H), 5.96 (dd, 1H, J=1.56 Hz, 10.28 Hz), 6.04 (s, 1H), 6.17(dd, 1H, J=10.32 Hz, 17.26 Hz), 6.34 (dd, 1H, J=1.56 Hz, 17.24 Hz), 7.27(m, 2H), 7.39 (m, 1H), 8.21 (s, 1H), 9.88 (s, 1H), 11.46 (s, 1H). ¹³CNMR (150 MHz DMSO-d₆):δ=18.378, 20.783, 25.640, 27.580, 43.681, 52.911,59.923, 61.683, 65.398, 82.697, 125.734, 127.057, 128.204, 128.279,129.068, 131.656, 132.482, 133.575, 138.866, 140.881, 157.001, 159.980,162.405, 162.633, 165.188, 165.469. HR-MS (m/z) calcd forC₃₅H₅₀ClN₇O₅SSi, [M]⁺=743.3052, [M+Na]⁺=766.2949, [M+Cs]⁺=876.2106;found [M+Na]⁺ m/z=766.2950−2.0 ppm, [M+Cs]⁺=876.2106+3.7 ppm.(*Determined using MeOD-d₄).

17. ABS of Cisplatin

a. Cisplatin Silyl Pro-drugs

Cisplatin is a hydrophilic drug that is water soluble. Because of itshydrophilic nature, it cannot easily be incorporated into polymerparticle compositions. For example, it is not miscible with the PLGApolymers, which are hydrophobic. One difficulty is achieving ahomogeneous delivery sheet with high loading of cisplatin in the PLGA.Any drug associated with the particle is lost quickly in a burst releaseprofile.

Cisplatin is more miscible in PEG hydrogel. However, because it is asmall molecule, it is difficult to retain drug in the PEG particle andit quickly leaks out over time. These problems can be overcome bymodifying cisplatin, or any hydrophilic small molecule, agent, drug,biologic or fragment thereof, etc. to be more compatible with PLGA orPEG particle systems.

One method is to attach a lipophilic molecule to the cisplatin to makeit more hydrophobic and more compatible with PLGA. By changing thelipophilicity of the cisplatin, it would be possible to cast homogeneousdelivery sheets with higher loading of drug. The attachment of thelipophilic entity would be through the cleavable silyl ether. Underacidic condition the lipid molecule would be cleaved and the drugreturned to its native state. PLGA particles with cisplatin encapsulatedwill have higher drug loading with improved release profiles.

A second method is directed to a co-polymerization of the drug into thePEG particle through the acid degradable silyl ether linkage. In thestructure below, X represents the covalently-bound residue of the drug.The acrylate group of the structure below can be used to polymerize thesilyl ether pro-drug into to the particle.

b. Starting Material Synthesis

In one embodiment, the Hard System (e.g. PLGA) involves conversion ofalcohols into lipid chains This allows for noncovalent incorporation ofhydrophobic cisplatin silyl ether pro-drugs into PRINT® nanoparticles,particularly into PLGA/PLLA particles. As discussed above, thehydrophilic nature of Cisplatin requires that it be made morehydrophobic for effective incorporation into the PLGA particle.

In one embodiment, the Soft System (e.g. Hydrogels) involves conversionof alcohols into polymerizable acrylates. This allows for covalentincorporation of cisplatin silyl ether pro-drugs into PRINT®nanoparticles, preferably a PEG hydrogel.

c. Targeted Release of Drug

18. ABS Pro-drugs via Covalent Carboxyl Linkage

The following examples depict the conversion of carboxylic acid/estermoieties of a drug into polymerizable asymmetric silyl acrylates. Thismodification provides a chemical handle for covalent incorporation ofsilyl ester pro-drugs into PRINT® nanoparticles.

a. Ibuprofen

¹H NMR and HR-MS data confirm the preparation of ^(i)Pr and ¹Bu silylester ibuprofen pro-drugs having the following structures:

b. Methotrexate

The synthetic strategy above will be used to synthesize pro-drugs ofchemotherapeutics containing at least one carboxylic acid moiety.Methotrexate is a class of anti-metabolite drugs used in the treatmentof cancer and auto immune diseases. Schemes 31, 32 and 33 depict aproposed synthesis of a silyl ester prodrug of methotrexate using atleast one available carboxyl group of methotrexate.

19. General Synthetic Routes for Preparing ABS Pro-drugs

a. Drugs Containing an Alcohol Moeity

In embodiments, modification of the alcohol with a dichlorodialkylsilane yielded a monochloro-silane intermediate, which was rapidlyconverted to a polymerizable monomer, for example, with the addition ofhydroxyl ethyl acrylate (HEA). In this non-limiting example, attachmentof the polymerizable HEA unit provided the chemical handle required forphotopolymerization during the fabrication of PRINT particles.

b. Drugs Containing an Amine Moeity

20. Biodegradation of PEG hydrogel Particles, Silyl Ether Pro-drugEncapsulation, Release, and In Vitro Analysis

The hydrolysis of PEG hydrogel particles under physiologically relevantconditions are shown in this example to estimate the fate of theparticles in vivo. The parameters examined were the amount ofphotoinitiator, the degradation rates of the bulk material compared tothe particles and the degradation conditions. Data is shown in Tables 2and 3 below.

The samples were degraded with the following protocol:

-   -   1) A ˜20 mg/ml sample of hydrogel was placed in a scintillation        vial.    -   2) The sample was immersed in 3 mL (excess buffer to accommodate        swelling) of pH 5 buffer.    -   3) A stir bar was added and the hot plate set to 900 rpm and        temperature of 37C.    -   4) A temperature probe and beaker of water was used to control        temperature fluctuation.    -   5) 200 ul aliquots were collected at 1 hr, 4 hrs, 1 day, 3        weeks, and 6 weeks.

Using GPC and visual inspection, the bulk samples were shown to degradeto polyacrylic acid and short PEG oligomer (1-10 units in length). Thehigher the photoinitiator concentration, the more quickly the bulksamples degraded. The higher amounts of photoinitiator resulted inshorter chain lengths and fewer entangled units resulting in moietieswhich should be able to be renally cleared. It is of note that renalclearance is typically between a molecular weight of 30-50K.

HP4A—Hydroxy PEG Acrylate with 4 ethylene glycol units

TABLE 2 Bulk sample composition Amount of HPA Amount of Photoinitiator(mg) (mg) 99.5 0.5 99.0 1.0 98.5 1.5 98.0 2.0Particles: 1 micron, 200×200 nm, 80×320

TABLE 3 Pre-particle Solution Composition: Amount of HPA Amount ofPhotoinitiator PEG-DA (mg) (mg) (mg) 89.5 0.5 10 89.0 1.0 10 88.5 1.5 1088.0 2.0 10

21. Degradation of ABS of Diisopropyl Gencitabine Silyl Ether (iPr-GEM)

A model degradation of an ABS pro-drug of gemcitabine attached via adi-isopropyl silyl ether linkage (iPr-GEM) was conducted. The resultsshow that the molecule is acid sensitive and reverts back to theoriginal starting materials. The HPLC chromatograms of this experiment,shown in FIGS. 3A-D, show that the starting material, HEA andcamptothecin (CPT), where converted to the Et-CPT ABS pro-drug in highpurity. Upon exposure to acid the silyl ether linkage degraded to yieldboth unmodified camptothecin and HEA

The ABS pro-drugs of gemcitabine were separately incorporated into“Trojan Horse” nanoparticles using particle replication in nonwettingtemplates a particle fabrication technique known as PRINT. PRINT is atop-down technique used to manufacture microparticles and nanoparticleswith well-defined shape and size. See, US 2009/0028910; US 2009/0061152;WO 2007/024323; US 2009/0220789; US 2007/0264481; US 2010;0028994; US2010;0196277; WO 2008/106503; US 2010/0151031; WO 2008/100304; WO2009/041652; PCT/US2010/041797; US 2008/0181958; WO 2009/111588; and WO2009/132206. Cylindrical nanoparticles with dimensions of 200 nm×200 nmwhere fabricated with 20 wt % of the ABS pro-drug, and the remainingbulk of the particle was comprised of a crosslinker (PEGi000diacrylate),a positive charge agent (aminoethyl methacrylate-hydrochloride,AEM-HCl), a fluorescent dye (FOA) and a photo-initiator (HCPK). Eachparticle fabricated with a gemcitabine ABS pro-drug had a typical sizerange of 280±10 nm and a zeta potential of 20±5.

A quantitative analysis of gemcitabine release was performed onparticles fabricated with Et-GEM, iPr-GEM and tBu-GEM. The particleswere degraded in solutions buffered at pH 5.0 and pH 7.4 and maintainedat 37° C. Aliquots of the solution were removed, filtered, and thesupernatant was injected into an HPLC. The plot of gemcitabine releaseversus time for each particle showed an increase in the rate of drugrelease when the particles were degraded under acidic conditions (FIG.4). Additionally, as the steric bulk around the silicon atom increasedthe rate of drug release decreased. For example, data on half-liferelease rates of different particles are shown (t-Bu GEM wasextrapolated) in Table 4 below. This demonstrates that the particles canrelease gemcitabine efficiently and the rate of release can be tunedbased on the substituents on the silicon atom. Furthermore, particlesdegraded under physiological conditions (pH 7.4) showed a significantlyslow rate of release when compared to the particles degraded at pH 5.0.

TABLE 4 Degradation half-lives (t_(1/2)) and relative rates of releasefrom 200 nm × 200 nm PRINT particles. Ethyl- Isopropyl- t-Butyl- GEM GEMGEM pH 5.0* 7.4* 5.0* 7.4* 5.0^(†) 7.4* t_(1/2) (h) 1.36 3.91 68.5 2746995 13055 Rel. 1 2.88 50.4 201 5143 9599 rate *Fitted to an exponentialgrowth. ^(†)Linear Fit

Intracellular degradation of the gemcitabine ABS pro-drugs was monitoredby cell viability experiments. This was accomplished by separatelydosing all three particle sets (Et-GEM, iPr-GEM, and tBu-GEM) onto theLnCAP cell line and comparing the cell viability against commerciallyavailable gemcitabine.

22. Composition and In Vitro Efficacy of Particles

a. Composition

PRINT particles where fabricated with a variety of compositions using adrug loading between 2 and 20 percent by weight. The effect of varyingconcentrations of CPT loading is depicted in FIG. 5. A 10-fold increaseof CPT (20%) resulted in a 10-fold increase in cellular toxicity. Due tofacile fabrication of particles containing 20 wt %, and the subsequentincrease in cellular toxicity, 20 wt % drug loading was selected as astandard particle load.

Cylindrical nanoparticles with dimensions of 200 nm×200 nm werefabricated with the ABS pro-drug according to PRINT methods, and theremaining bulk of the particle was comprised of a crosslinker(PEGi000diacrylate), a positive charge agent (aminoethylmethacrylate-hydrochloride, AEM-HCl), a fluorescent dye (fluoresceino-acrylate, FOA) and a photo-initiator (1-hydroxycyclohexyl phenylketone, HCPK).

TABLE 5 Camptothecin Particle Compositions Et-CPT-2 Et-CPT-20PEG₁₀₀₀DiAcrylate 76 58 AEM-HCl 20 20 FOA 1 1 HCPK 1 1 Pro-Drug 2 20 100100 Theor. wt % of (1.27) (12.7) Camptothecin

TABLE 6 Gemcitabine Particle Compositions Et-GEM iPr-GEM tBu-GEM BlanksPEG₁₀₀₀DiAcrylate 58 58 58 78 AEM-HCl 20 20 20 20 FOA 1 1 1 1 HCPK 1 1 11 Pro-Drug 20 20 20 0 100 100 100 100 Theor. wt % of (11.36) (10.70)(10.14) (0.00) Gemcitabine

b. Cell Viability Assay

The cytotoxicity of each particle was determined using a CellTiter-Gloluminescent cell viability assay after a 72 hour incubation time (FIG.6).

The data from the cell viability assay show that particles containingEt-GEM or iPr-GEM performed as well, if not better, than the freegemcitabine. In fact, particles containing the Et-GEM ABS pro-drugactually outperformed the free gemcitabine throughout the in vitro cellassay. This superior efficacy may be due to rapid particleinternalization of the positively charged particles, and rapid releaseof the gemcitabine upon exposure to an acidic cellular compartment.Remarkably, the particles fabricated from the tBu-GEM ABS pro-drugshowed almost negligible amounts of cytotoxicity, even at extremely highdrug concentrations. This further establishes the tenability of thedisclosed ABS pro-drugs. Each can be tuned independently to degraderapidly, moderately, or even not at all.

Asymmetric bifunctional silyl ether pro-drugs were synthesized andanalyzed as potential materials for controlled drug delivery innanoparticles. Using one-step synthesis, numerous pro-drugs from thechemotherapeutics camptothecin, dasatinib, and gemcitabine wereprepared. These ABS pro-drugs were placed under acidic conditions, suchas those found under physiological conditions, and subsequent todegradation of the reversible covalent linkage(s), the pro-drug revertedback to the original active form of the chemotherapeutic. The ABSpro-drugs of gemcitabine were incorporated into 200 nm PRINTnanoparticles and showed controlled and tunable released of gemcitabine.The rate of release increased as the steric bulk of the substituent onthe Si atom decreased; Rate of Release: Et-GEM>iPr-GEM>>tBu-GEM). It wasfound that the release of the particle-bound drug was accelerated uponexposure to acidic condition similar to those found in the cellularendocytic cycle. These ABS pro-drugs can be incorporated intonanoparticles and medical devices capable of releasing drugs in acontrolled and tunable fashion.

c. Particle Fabrication

A monomer solution (5% in dimethylformamide (DMF)) consisting of thefollowing components is prepared as shown in Table 7.

TABLE 7 No Prodrug With Prodrug Monomer (Wt %) (Wt %) PEG₁₀₀₀dimethacrylate 78 58 2-Aminoethyl methacrylate 20 20 hydrochlorideFluorescein o-acrylate 1 1 1-Hydroxycyclohexyl phenyl ketone 1 1Diisopropyl gemcitabine prodrug 0 20A monomer film is cast upon a sheet of poly(ethylene terephthalate)(PET) with a mayer rod (#2) and dried with heat. The PET sheet (monomerfilm) and mold are laminated under pressure and then delaminated. Themold is laminated with a fresh sheet of PET and then exposed to UVirradiation for 4 minutes. The mold is removed, transferring particlesonto the PET. Particles are collected from the PET by gently moving coldDulbecco's phosphate buffered saline (DPBS) along the sheet with a cellscraper. The harvested particles are washed twice with cold DPBS bycentrifugation.

d. Ligand Conjugation to Particles

The particles are washed once with DMF by centrifugation and thenresuspended in DMF. Particles are reacted with NHS-PEG₅₀₀₀-biotin in DMFin the presence of pyridine for 2 h. The particles are then reacted withacetic anhydride to quench unreacted amines on the particle surface. Theparticles are washed once with DMF and twice with DPBS by centrifugationand then resuspended in DPBS. To attach avidin, particles in DPBS areshaken with UltraAvidin for 1 h, followed by two washings with DPBS bycentrifugation. To conjugate a ligand (either OKT9- or IgG-biotin),particles are reacted with the ligand in DPBS for 30 min at roomtemperature and then overnight at 4° C. Particles are washed with DPBSby centrifugation to remove unbound ligand.

e. In Vitro Targeting

H460 cells, a lung cancer cell line with high expression of thetransferrin receptor (TfR), were incubated first with varyingconcentrations of free OKT9 for 1 h at 37° C.

Targeted particles were then incubated with the cells and free OKT9 for4 h at 37° C. Samples were analyzed by flow cytometry. As seen in FIG.12, without competing free ligand, OKT9-targeted particles bound to thecellular surface and were internalized. However, in the presence of freeligand, OKT9-targeted particles were unable to bind to cells as the TfRon the cellular surface were already bound by free ligand. Increasingconcentrations of free OKT9 inhibited greater binding andinternalization of OKT9-targeted particles, competitively binding withthe TfR. The results suggest that OKT9-targeted particles selectivelybind the TfR and internalize into H460 cells via receptor-mediatedendocytosis.

Selective targeting of OKT9-targeted particles was observed by confocalmicroscopy as shown in FIG. 13. Targeted particles were incubated withH460 cells for 4 and 24 h. The cellular nucleus was stained with4′,6-diamidino-2-phenylindole (DAPI), and acidic vesicles within thecell were stained with Lysotracker Red; particles were labeled withfluorescein o-acrylate. At 4 h, binding and some internalization ofOKT9-targeted particles is observed, while increased internalization andcolocalization is seen at 24 h. IgG-targeted particles do not bind andinternalize into the cells.

f. In Vitro Cytotoxity

Targeted particles containing the prodrug were incubated with H460 cellsfor 1 h at 37° C. to facilitate selective binding of the particles tothe TfR. Unbound particles were then removed, and the cells were allowedto incubate at 37° C. for the remainder of 72 h, after whichcytotoxicity profiles of cells treated with particles were analyzed witha luminescence assay. OKT9-targeted particles exhibited enhancedcytotoxicity relative to free gemcitabine (FIG. 14). They also exhibitedspecific cytotoxicity compared to IgG-targeted particles due to theselective TfR targeting of the particles for improved internalizationand consequent prodrug degradation for drug release.

The following references are incorporate herein by reference in theirentirety: Reversible hydrophobic modification of drugs for improveddelivery to cells, Monahan, Sean D.; Subbotin, Vladimir; Neal, Zane C.;Budker, Vladimir G.; Budker, Tatyana, U.S. Pat. Appl. Publ. (2009), US20090074885 A1 filed 2009 03 19; Targeted drug delivery by labilehydrophobic modification of drugs, Monahan, Sean D.; Budker, VladimirG.; Neal, Zane C.; Subbotin, Vladimir, U.S. Pat. Appl. Publ. (2005), US20050054612 A1 filed 2005 03 10; Protein and peptide delivery tomammalian cells in vitro, Monahan, Sean D.; Budker, Vladimir G.; Ekena,Kirk; Nader, Lisa, U.S. Pat. Appl. Publ. (2004), US 20040151766 A1 filed2004 08 05; J. Med. Chem. 1993, 36, 3087-3097 3087. CatalyticFunctionalization of Polymers: A Novel Approach to Site SpecificDelivery of Misoprostol to the Stomach, Samuel J. Tremont, Paul W.Collins, William E. Perkins, Rick L. Fenton, Denis Forster, Martin P.McGrath; Grace M. Wagner, Alan F Gasiecki, Robert G. Bianchi, JacquelynJ. Casler, Cecile M. Ponte, James C. Stolzenbach, Peter H. Jones, JaniceK. Gard, and William B. Wise, Monsanto Corporate Research, 800 NorthLindbergh Boulevard, St. Louis, Mo., 63167, and Searle DiscoveryResearch, 4901 Searle Parkway, Skokie, Ill. 60077.

Throughout this specification and the claims, the words “comprise,”“comprises,” and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise.

As used herein, the term “about,” when referring to a value is meant toencompass variations of, in some embodiments ±20%, in some embodiments±10%, in some embodiments ±5%, in some embodiments ±1%, in someembodiments ±0.5%, and in some embodiments ±0.1% from the specifiedamount, as such variations are appropriate to perform the disclosedmethods or employ the disclosed compositions.

All publications, patent applications, patents, and other references areherein incorporated by reference to the same extent as if eachindividual publication, patent application, patent, and other referencewas specifically and individually indicated to be incorporated byreference. It will be understood that, although a number of patentapplications, patents, and other references are referred to herein, suchreference does not constitute an admission that any of these documentsforms part of the common general knowledge in the art.

Although the foregoing subject matter has been described in some detailby way of illustration and example for purposes of clarity ofunderstanding, it will be understood by those skilled in the art thatcertain changes and modifications can be practiced within the scope ofthe appended claims

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

The which is claimed:
 1. A method for making a particle comprising: a.first, covalently linking a monomer and a silyl via an O, N, S, orcarboxyl of said monomer to form a silyl functionalized monomer; b.second, covalently linking a nucleic acid to said silyl functionalizedmonomer to form a first nucleic acid-silyl functionalized monomer; andc. third, forming a particle from the first nucleic acid-silylfunctionalized monomer of step b, wherein the nucleic acid-silylfunctionalized monomer has the structure:

wherein R^(1′)and R^(2′)are independently alkyl; wherein M is a monomerselected from the group consisting of 2-hydroxyethyl acrylate,2-hydroxyethyl methacrylate , vinyl pyrrolidone, acrylic acid, ethyleneoxide, poly(ethylene oxide), vinyl alcohol, a protein, an amino acid,and a polysaccharide; wherein X_(a) and X_(b) are independently selectedfrom the group consisting of O, NH, S, and a carboxyl; and whereinR^(3′)is a nucleic acid.
 2. The method of claim 1, wherein forming theparticle comprises molding the first nucleic acid-silyl functionalizedmonomer in a mold cavity.
 3. The method of claim 1, wherein forming theparticle further comprises associating a biocompatible polymer with thefirst nucleic acid-silyl functionalized monomer through a covalent link,physical entanglement, electrostatic association or hydrostaticassociation.
 4. The method of claim 1, further comprising a secondnucleic acid-silyl functionalized monomer.
 5. The method of claim 4,wherein the second nucleic acid-silyl functionalized monomer comprisesthe same or different monomer or nucleic acid as the first nucleicacid-silyl functionalized monomer.
 6. The method of claim 1, wherein thenucleic acid comprises a ratio of 0.1 mg of nucleic acid to 1 mg ofparticle.
 7. The method of claim 1, wherein the nucleic acid-silylfunctionalized monomer comprises between 1 wt % and 50 wt % of theparticle.
 8. The method of claim 1, wherein the nucleic acid-silylfunctionalized monomer comprises between 1 wt % and 40 wt % of of theparticle.
 9. The method of claim 1, wherein the nucleic acid-silylfunctionalized monomer comprises between 2 wt % and 20 wt % of theparticle.
 10. The method of claim 4, wherein forming the particlecomprises molding the nucleic acid-silyl functionalized monomers in amold cavity.
 11. The method of claim 1, wherein the nucleic acid isselected from the group consisting of RNA, siRNA, DNA, and combinationsthereof.
 12. The method of claim 1, wherein X_(a) and X_(b) are both O.13. The method of claim 1, wherein R^(1′)and R^(2′)are independentlyselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
 14. Themethod of claim 1, wherein the particle has a release rate ofapproximately 4 times slower at pH 7.4 relative to a release rate at pH5.0.
 15. The method of claim 1, wherein the particle has a release rateof approximately 50.4 times slower at pH 5.0 and 201 times slower at pH7.4 relative to a release rate at pH 5.0 wherein R^(1′)and R^(2′)areethyl.